U.S. patent application number 10/047941 was filed with the patent office on 2002-10-17 for biodegradable polymers chain-extended by phosphates, compositions, articles and methods for making and using the same.
Invention is credited to English, James P., Leong, Kam W., Mao, Hai-Quan, Zhao, Zhong.
Application Number | 20020151617 10/047941 |
Document ID | / |
Family ID | 25261018 |
Filed Date | 2002-10-17 |
United States Patent
Application |
20020151617 |
Kind Code |
A1 |
Mao, Hai-Quan ; et
al. |
October 17, 2002 |
Biodegradable polymers chain-extended by phosphates, compositions,
articles and methods for making and using the same
Abstract
Biodegradable polymers are described comprising the recurring
monomeric units shown in formula I or II: 1 wherein X is --O-- or
--NR'--, where R' is H or alkyl; L is a branched or straight chain
aliphatic group having from 1-20 carbon atoms; M.sub.1 and M.sub.2
are each independently (1) a branched or straight chain aliphatic
group having from 1-20 carbon atoms; or (2) a branched or straight
chain, oxy-, carboxy- or amino-aliphatic group having from 1-20
carbon atoms; Y is --O--, --S-- or --NR'--, where E' is H or alkyl;
R is H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or
heterocycloxy; the molar ratio of x:y is about 1; the molar ratio
n:(x or y) is between about 200:1 and 1:200; and the molar ratio
q:r is between about 1:99 and 99:1; wherein said biodegradable
polymer is biocompatible before and upon biodegradat. Processes for
preparing the polymers, compositions containing the polymers and
biologically active substances, articles useful for implantation or
injection into the body fabricated from the compositions, and
methods for controllably releasing biologically active substances
using the polymers, are also described.
Inventors: |
Mao, Hai-Quan; (Towson,
MD) ; Leong, Kam W.; (Ellicott City, MD) ;
Zhao, Zhong; (Baltimore, MD) ; English, James P.;
(Chelsea, AL) |
Correspondence
Address: |
FOLEY, HOAG & ELIOT LLP
ONE POST OFFICE SQUARE
BOSTON
MA
02109
US
|
Family ID: |
25261018 |
Appl. No.: |
10/047941 |
Filed: |
January 15, 2002 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10047941 |
Jan 15, 2002 |
|
|
|
09654326 |
Sep 1, 2000 |
|
|
|
6376644 |
|
|
|
|
09654326 |
Sep 1, 2000 |
|
|
|
09053649 |
Apr 2, 1998 |
|
|
|
6166173 |
|
|
|
|
09053649 |
Apr 2, 1998 |
|
|
|
08832217 |
Apr 3, 1997 |
|
|
|
Current U.S.
Class: |
523/115 ;
528/287 |
Current CPC
Class: |
A61K 9/1647 20130101;
A61L 17/12 20130101; C08G 63/912 20130101; Y10S 623/924 20130101;
A61K 9/0024 20130101; C08G 63/6922 20130101; A61L 26/0019 20130101;
A61L 27/18 20130101; A61L 26/0019 20130101; C08L 85/02 20130101;
A61L 27/18 20130101; C08L 85/02 20130101 |
Class at
Publication: |
523/115 ;
528/287 |
International
Class: |
A61F 002/00; C08G
063/68 |
Claims
We claim:
1. A biodegradable polymer comprising the recurring monomeric units
shown in formula I or II: 18wherein: X is --O-- or --NR'--, where
R' is H or alkyl; M.sub.1 and M.sub.2 are each independently (1) a
branched or straight chain aliphatic group having from 1-20 carbon
atoms; or (2) a branched or straight chain, oxy-, carboxy- or
amino-aliphatic group having from 1-20 carbon atoms; Y is --O--,
--S-- or --NR'--; L is a branched or straight chain aliphatic group
having from 1-20 carbon atoms; R is H, alkyl, alkoxy, aryl,
aryloxy, ieterccyclic or heterocycloxy; the molar ratio of x:y is
about 1; the molar ratio n:(x or y) is between about 200:1 and
1:200; and the molar ratio q:r is between about 1:99 and 99:1;
wherein said biodegradable polymer is biocompatible before and upon
biodegradation.
2. The polymer of claim 1 wherein each of M.sub.1 and L is a
branched or straight chain alkylene group.
3. The polymer of claim 1 wherein each of M.sub.1 and L has from 1
to 7 carbon atoms.
4. The polymer of claim 1 wherein M.sub.1 is an ethylene group or a
methyl-substituted methylene group, and L is an ethylene group.
5. The polymer of claim 1 wherein R is an alkyl group, an alkoxy
group, a phenyl group, a phenoxy group, or a heterocycloxy
group.
6. The polymer of claim 1 wherein R is an alkoxy group having from
1 to 7 carbon atoms.
7. The polymer of claim 1 wherein R is an ethoxy group.
8. The polymer of claim 1 wherein each of M.sub.1 and M.sub.2 is a
branched or straight chain alkylene group.
9. The polymer of claim 1 wherein at least one of M.sub.1 and
M.sub.2 is an alkylene or alkoxylene group having a formula
selected from the group consisting of --(CH.sub.2).sub.a--,
--(CH.sub.2).sub.a--O--, and
--(CH.sub.2).sub.a--O--(CH.sub.2).sub.b--, wherein each of a and b
is 1-7.
10. The polymer of claim 1 wherein at least one of M.sub.1 and
M.sub.2 has the formula: --CHR.sup.2--CO--O--CHR.sup.3--, wherein
R.sup.2 and R.sup.3 are each independently H, alkyl, alkoxy, aryl;
aryloxy, heterocyclic or heterocycloxy.
11. The polymer of claim 1 wherein each of M.sub.1 and M.sub.2 has
from 1 to 7 carbon atoms.
12. The polymer of claim 1 wherein X is --O--.
13. The polymer of claim 1 wherein X is --NR'--.
14. The polymer of claim 1 wherein: M.sub.1 and M.sub.2 are each an
alkylene or alkoxylene group; L is an alkylene group; X is --O--;
and R is an alkoxy group.
15. The polymer of claim 1 wherein the molar ratio x:y is about
1.
16. The polymer of claim 1 wherein the molar ratio q:r is about
1:99 and 99:1.
17. The polymer of claim 1 wherein each of x and y is about 1 to
1,000.
18. The polymer of claim 1 wherein the molar ratio n:(x or y) is
between about 100:1 and 1:100.
19. The polymer of claim 1 wherein said polymer is prepared by melt
polymerization.
20. The polymer of claim 1 wherein said polymer comprises
additional biocompatible monomeric units.
21. The polymer of claim 1 wherein said polymer is soluble in at
least one of the solvents selected from the group consisting of
acetone, dimethylene chloride, chloroform, ethyl acetate, DMAC,
N-methyl pyrrolidone, dimethylformamide and dimethylsulfoxide.
22. A process for preparing a biodegradable polymer comprising the
recurring monomeric units of formula I or II: 19wherein: X is --O--
or --NR'--, where R' is H or alkyl; M.sub.1 and M.sub.2 are each
independently (1) a branched or straight chain aliphatic group
having from 1-20 carbon atoms; or (2) a branched or straight chain,
oxy-, carboxy- or amino-aliphatic group having from 1-20 carbon
atoms; Y is --O--, --S-- or --NR'--; L is a branched or straight
chain aliphatic group having from 1-20 carbon atoms; R is H, alkyl,
alkoxy, aryl, aryloxy, heterocyclic or heterocycloxy; the molar
ratio of x:y is about 1; the molar ratio n: (x or y) is between
about 200:1 and 1:200; and the molar ratio q:r is between about
1:99 and 99:1; wherein said biodegradable polymer is biocompatible
before and upon biodegradation; wherein said biodegradable polymer
is biocompatible before and upon biodegradation, said process
comprising the steps of: (a) reacting at least one heterocyclic
ring compound having formula III, IV or V: 20wherein M.sub.1,
M.sub.2 and X are as defined above, with an initiator having the
formula: H--Y--L--Y--H, wherein Y and L are as defined as above, to
form a prepolymer of formula VI or VII, shown below: 21wherein X,
M.sub.1, M.sub.2, Y, L, R, x, y, q and r are as defined above; and
b) further reacting said prepolymer of formula III, IV or V with a
phosphorodihalidate of formula VIII; 22where "halo" is Br, Cl or I;
and R is-as defined. above, to form said polymer of formula I or
II.
23. The process of claim 22 wherein each of M.sub.1 and L is a
branched or straight chain alkylene group having from 1 to 7 carbon
atoms.
24. The process of claim 22 wherein M.sub.1 is an ethylene group or
a methyl-substituted methylene group, and L is an ethylene
group.
25. The process of claim 22 wherein R is an alkoxy group having
from 1 to 7 carbon atoms.
26. The process of claim 22 wherein R is an ethoxy group.
27. The process of claim 22 wherein each of M.sub.1 and M.sub.2 is
a branched or straight chain alkylene group.
28. The process of claim 22 wherein at least one of M.sub.1 and
M.sub.2 is an alkylene or alkoxylene group having a formula
selected from the group consisting of --(CH.sub.2).sub.a--,
--(CH.sub.2).sub.a--O--, and
--(CH.sub.2).sub.a--O--(CH.sub.2).sub.b--, wherein each of a and b
is 1-7.
29. The process of claim 22 wherein at least one of M.sub.1 and
M.sub.2 has the formula: --CHR.sup.2--CO--O--CHR.sup.3--, wherein
R.sup.2 and R.sup.3 are each independently H, alkyl, alkoxy, aryl,
aryloxy, heterocyclic or heterocycloxy.
30. The process of claim 22 wherein each of M.sub.1 and M.sub.2 has
from 1 to 7 carbon atoms.
31. The process of claim 22 wherein X is --O--.
32. The process of claim 22 wherein X is --NR'--.
33. The process of claim 22 wherein: M.sub.1 and M.sub.2 are each
an alkylene or alkoxylene group; L is an alkylene group; X is
--O--; and R is an alkoxy group.
34. The process of claim 22 wherein the molar ratio x:y is about
1.
35. The process of claim 22 wherein the molar ratio q:r is about
1:99 and 99:1.
36. The process of claim 22 wherein each of x and y are about 1 to
1000.
37. The process of claim 22 wherein the molar ratio n:(x or y) is
from about 100:1 to about 1:100.
38. The process of claim 22 wherein said reacting step (a) takes
place at a temperature about 0 to about +235.degree. C.
39. The process of claim 22 wherein said reacting step (a) takes
place during a time between about 1 hour to seven days.
40. The process of claim 22 wherein, in said initiator, L is
substituted with one or more additional Y--H-containing
substituents, wherein Y is as defined above.
41. The process of claim 22 wherein a catalyst is present during
said reacting step (a).
42. The process of claim 22 wherein, during the polymerization step
(b), an acid acceptor is present.
43. The process of claim 22 wherein said polymerization of step (b)
takes place at a temperature between about -40 and 150.degree.
C.
44. The process of claim 22 wherein said polymerization of step (b)
takes place during a time of about 30 minutes to 24 hours.
45. The process of claim 22 wherein said polymer of formula I or II
is purified by quenching a solution of said polymer with a
non-solvent or a partial solvent.
46. A biosorbable suture comprising the polymer of claim 1.
47. An orthopedic appliance, bone cement or bone wax for repairing
injuries to bone and connective tissue comprising the polymer of
claim 1.
48. A laminate for degradable or non-degradable fabrics comprising
the polymer of claim 1.
49. A coating for an implantable device comprising the polymer of
claim 1.
50. A biodegradable polymer composition comprising: (a) at least
one biologically active substance and (b) a polymer having the
recurring monomeric units shown in formula I or II: 23wherein: X is
--O-- or --NR'--, where R' is H or alkyl; M.sub.1 and M.sub.2 are
each independently (1) a branched or straight chain aliphatic group
having from 1-20 carbon atoms; or (2) a branched or straight chain,
oxy-, carboxy- or amino-aliphatic group having from 1-20 carbon
atoms; Y is --O--, --S-- or --NR'--; L is a branched or straight
chain aliphatic group having from 1-20 carbon atoms; R is H, alkyl,
alkoxy, aryl, aryloxy, heterocyclic or heterocycloxy; the molar
ratio of x:y is about 1; the molar ratio n:(x or y) is between
about 200:1 and 1:200; and the molar ratio q:r is between about
1:99 and 99:1; wherein said biodegradable polymer is biocompatible
before and upon biodegradation.
51. The polymer composition of claim 50 wherein each of M.sub.1 and
L is a branched or straight chain alkylene group.
52. The polymer composition of claim 50 wherein M, is an ethylene
group or a methyl-substituted methylene group, and L is an ethylene
group.
53. The polymer composition of claim 50 wherein R is an alkyl
group, an alkoxy group, a phenyl group, a phenoxy group, or a
heterocycloxy group.
54. The polymer composition of claim 50 wherein R is an alkoxy
group.
55. The polymer composition of claim 50 wherein each of M.sub.1 and
M.sub.2 is a branched or straight chain alkylene group.
56. The polymer composition of claim 50 wherein at least one of
M.sub.1 and M.sub.2 is an alkylene or alkoxylene group having a
formula selected from the group consisting of --(CH.sub.2).sub.a--,
--(CH.sub.2).sub.a--C--, and
(CH.sub.2).sub.a--O--(CH.sub.2).sub.b--, wherein each of a and b is
1-7.
57. The polymer compositions of claim 50 wherein at least one of
M.sub.1 and M.sub.2 has the formula:
--CHR.sup.2--CO--O--CHR.sup.3--, wherein R.sup.2 and R.sup.3 are
each independently H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or
heterocycloxy.
58. The polymer compositions of claim 50 wherein each of M.sub.1
and M.sub.2 has from 1 to 7 carbon atoms.
59. The polymer compositions of claim 50 wherein X is --O--.
60. The polymer compositions of claim 50 wherein X is --NR'--.
61. The polymer compositions of claim 50 wherein: M.sub.1 and
M.sub.2 are each an alkylene or alkoxylene group; L is an alkylene
group; X is --O--; and R is an alkoxy group.
62. The polymer compositions of claim 50 wherein the molar ratio
x:y is about 1.
63. The polymer compositions of claim 50 wherein the molar ratio
q:r is about 1:99 and 99:1.
64. The polymer composition of claim 50 wherein each of x and y is
about 1 to 1,000.
65. The polymer composition of claim 50 wherein the ratio n:(x or
y) is from about 100:1 to about 1:100.
66. The polymer composition of claim 50 wherein said polymer is
prepared by melt polymerization.
67. The polymer composition of claim 50 wherein said polymer
comprises additional biocompatible monomeric units.
68. The polymer composition of claim 50 wherein said polymer is
soluble in at least one of the solvents selected from the group
consisting of acetone, dimethylene chloride, chloroform, ethyl
acetate, DMC, N-methyl pyrrolidone, dimethylformamide and
dimethylsulfoxide.
69. The polymer composition of claim 50 wherein said biologically
active substance is selected from the group consisting of
polysaccharides, growth factors, hormones, anti-angiogenesis
factors, interferons or cytokines, and pro-drugs of these
substances.
70. The polymer composition of claim 50 wherein said biologically
active substance is a therapeutic drug or pro-drug.
71. The polymer composition of claim 70 wherein said drug is
selected from the group consisting of anti-neoplastic agents,
antibiotics, anti-virals, anti-fungals, anti-inflammatories, and
anticoagulants.
72. The polymer composition of claim 71 wherein the anti-neoplastic
agent is paclitaxel.
73. The polymer composition of claim 50 wherein said biologically
active substance and said polymer form a homogeneous matrix.
74. The polymer composition of claim 50 wherein said polymer is
characterized by a release rate of the biologically active
substance in vivo controlled at least partially as a function of
hydrolysis of the phosphoester bond of the polymer during
biodegradation.
75. An article useful for implantation, injection, or otherwise
being placed totally or partially within the body, said article
comprising a biodegradable polymer composition comprising: (a) at
least one biologically active substance and (b) a polymer having
the recurring monomeric units shown in formula I or II: 24wherein:
x is --O-- or --NR'--, where R' is H or alkyl; M.sub.1 and M.sub.2
are each independently (1) a branched or straight chain aliphatic
group having from 1-20 carbon atoms; or (2) a branched or straight
chain, oxy-, carboxy- or amino-aliphatic group having from 1-20
carbon atoms; Y is --O--, --S-- or --NR'--; L is a branched or
straight chain aliphatic group having from 1-20 carbon atoms; R is
H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or heterocycloxy; the
molar ratio of x:y is about 1; the molar ratio n:(x or y) is
between about 200:1 and 1:200; and the molar ratio q:r is between
about 1:99 and 99:1; wherein said biodegradable polymer is
biocompatible before and upon biodegradation.
76. The article of claim 75 wherein each of M.sub.1 and L is a
branched or straight chain alkylene group.
77. The article of claim 75 wherein each of M.sub.1 and L has from
1 to 7 carbon atoms.
78. The article of claim 75 wherein R is an alkyl group, an alkoxy
group, a phenyl group, a phenoxy group, or a heterocycloxy
group.
79. The article of claim 75 wherein R is an alkoxy group.
80. The article of claim 75 wherein each of M.sub.1 and M.sub.2 is
a branched or straight chain alkylene group.
81. The article of claim 75 wherein at least one of M.sub.1 and
M.sub.2 is an alkylene or alkoxylene group having a formula
selected from the group consisting of --(CH.sub.2).sub.a--,
--(CH.sub.2).sub.a--O--, and
--(CH.sub.2).sub.a--O--(CH.sub.2).sub.b--, wherein each of a and b
is 1-7.
82. The article of claim 75 wherein at least one of M.sub.1 and
M.sub.2 has the formula CHR.sup.2--CO--O--CHR.sup.3--, wherein
R.sup.2 and R.sup.3 are each independently H, alkyl, alkoxy, aryl,
aryloxy, heterocyclic or heterocycloxy.
83. The article of claim 75 wherein each of M.sub.1 and M.sub.2 has
from 1 to 7 carbon atoms.
84. The article of claim 75 wherein X is --O--.
85. The article of claim 75 wherein X is --NR'--.
86. The article of claim 75 wherein: M.sub.1 and M.sub.2 are each
an alkylene or alkoxylene group; L is an alkylene group; X is
--O--; and R is an alkoxy group.
87. The article of claim 75 wherein the molar ratio x:y is about
1.
88. The article of claim 75 wherein the molar ratio q:r is about
1:99 and 99:1.
89. The polymer composition of claim 75 wherein each of x and y is
about 1 to 1,000.
90. The article of claim 75 wherein the molar ratio n:(x or y) is
from about 100:1 to about 1:100.
91. The article of claim 75 wherein said polymer is prepared by
melt polymerization.
92. The article of claim 75 wherein said polymer comprises
additional biocompatible monomeric units.
93. The article of claim 75 wherein said polymer is soluble in at
least one of the solvents selected from the group consisting of
acetone, dimethylene chloride, chloroform, ethyl acetate, DMAC,
N-methyl pyrrolidone, dimethylformamide and dimethylsulfoxide.
94. The article of claim 75 wherein said biologically active
substance is selected from the group consisting of polysaccharides,
growth factors, hormones, anti-angiogenesis factors, interferons or
cytokines, and pro-drugs of these substances.
95. The article of claim 75 wherein said biologically active
substance is a therapeutic drug or pro-drug.
96. The article of claim 75 wherein said biologically active
substance is selected from the group consisting of anti-neoplastic
agents, antibiotics, anti-virals, anti-fungals,
anti-inflammatories, anticoagulants, and pro-drugs of these
substances.
97. The article of claim 7S wherein the anti-neoplastic agent is
paclitaxel.
98. The article of claim 75 wherein said biologically active
substance and said polymer form a homogeneous matrix.
99. The article of claim 75 wherein said biologically active
substance is encapsulated within said polymer.
100. The article of claim 75 wherein said polymer is characterized
by a release rate of the biologically active substance in vivo
controlled at least partially as a function of hydrolysis of the
phosphoester bond of the polymer upon biodegradation.
101. The article of claim 75 wherein said article is adapted for
implantation or injection into the body of an animal.
102. The article of claim 75 wherein said article is a
microsphere.
103. The article of claim 75 wherein said article results in
minimal tissue irritation when implanted or injected into
vasculated tissue.
104. The article of claim 75 wherein said article is in the form of
a laminate for degradable fabric.
105. The article of claim 75 wherein said article is in the form of
a biosorbable suture, a material for repairing bone injuries, or a
coating on an implant device.
106. A method for the controlled release of a biologically active
substance comprising the steps of: (a) combining the biologically
active substance with a biodegradable polymer having the recurring
monomeric units shown in formula I or II: 25where in X is --O-- or
--NR'--, where R' is H or alkyl; M.sub.1 and M.sub.2 are each
independently (1) a branched or straight chain aliphatic group
having from 1-20 carbon atoms; or (2) a branched or straight chain,
oxy-, carboxy- or amino-aliphatic group having from 1-20 carbon
atoms; Y is --O--, --S-- or --NR'--; L is a branched or straight
chain aliphatic group having from 1-20 carbon atoms; R is H, alkyl,
alkoxy, aryl, aryloxy, heterocyclic or heterocycloxy; the molar
ratio of x:y is about 1; the molar ratio n:(x or y) is between
about 200:1 and 1:200; and the molar ratio q:r is between about
1:99 and 99:1; wherein said biodegradable polymer is biocompatible
before and upon biodegradation, to form an admixture; (b) forming
said admixture into a shaped, solid article or microsphere; and (c)
implanting or injecting said solid article or microsphere in vivo
at a preselected site, such that the solid implanted or injected
matrix is in at least partial contact with a biological fluid.
107. The method of claim 106 wherein each of R and L is a branched
or straight chain alkylene group.
108. The method of claim 106 wherein R' is an alkoxy group.
109. The method of claim 106 wherein each of M.sub.1 and M.sub.2 is
a branched or straight chain alkylene group.
110. The method of claim 106 wherein at least one of M.sub.1 and
M.sub.2 is an alkylene or alkoxylene group having a formula
selected from the group consisting of --(CH.sub.2).sub.a--,
--(CH.sub.2).sub.a--O--, and
--(CH.sub.2).sub.a--O--(CH.sub.2).sub.b--, wherein each of a and b
is 1-7.
111. The method of claim 106 wherein at least one of M.sub.1 and
M.sub.2 has the formula: --CHR.sup.2--CO--O--CHR.sup.3--, wherein
R.sup.2 and R.sup.3 are each independently H, alkyl, alkoxy, aryl,
aryloxy, heterocyclic or heterocycloxy.
112. The method of claim 106 wherein each of M.sub.1 and M.sub.2
has from 1 to 7 carbon atoms.
113. The method of claim 106 wherein X is --O--.
114. The method of claim 106 wherein X is --NR'--.
115. The method of claim 106 wherein: M.sub.1 and M.sub.2 are each
an alkylene or alkoxylene group; L is an alkylene group, X is
--O--; and R is an alkoxy group.
116. The method of claim 106 wherein the molar ratio x:y is about
1.
117. The method of claim 106 wherein the molar ratio q:r is about
1:99 and 99:1.
118. The polymer composition of claim 106 wherein each of x and y
is about 1 to 1,000.
119. The method of claim 106 wherein the-molar ratio n:(x or y) is
from about 100:1 to about 1:100.
120. The method of claim 106 wherein said polymer comprises
additional biocompatible monomeric units.
121. The method of claim 106 wherein said biologically active
substance is selected from the group consisting of polysaccharides,
growth factors, hormones, anti-angiogenesis factors and other
anti-neoplastic agents, interferons or cytokines, and pro-drugs of
these substances.
122. The method of claim 106 wherein the anti-neoplastic agent is
paclitaxel.
123. The method of claim 106 wherein said biologically active
substance is a therapeutic drug or pro-drug.
124. The method of claim 106 wherein said drug is selected from the
group consisting of chemotherapeutic agents, antibiotics,
anti-virals, anti-fungals, anti-inflammatories, and
anticoagulants.
125. The method of claim 106 wherein said biologically active
substance and said polymer form a homogeneous matrix.
126. The method of claim 106 further comprising encapsulating said
biologically active substance within said polymer.
127. The method of claim 106 wherein said polymer is characterized
by a release rate of the biologically active substance in vivo
controlled at least partly as a function of hydrolysis of the
phosphoester bond of the polymer upon degradation.
128. The method of claim 106 wherein said article is non-toxic and
results in minimal tissue irritation when implanted or injected
into vasculated tissue.
129. The method of claim 106 wherein said article is in the form of
microspheres.
130. The method of claim 106 wherein said article is in the form of
a laminate for degradable fabric.
131. The method of claim 106 wherein said polymer composition is
used as a coating for an implant.
132. The method of claim 106 wherein the polymer composition is
used as a barrier for adhesion prevention.
133. The method of claim 106 wherein said polymer composition is
fabricated as a tube for nerve generation.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to biodegradable polymer
compositions, in particular those containing both phosphate and
ester linkages in the polymer backbone and that degrade in vivo
into non-toxic residues. The polymers of the invention are
particularly useful as implantable medical devices and drug
delivery systems.
[0003] 2. Description of the Prior Art
[0004] Biocompatible polymeric materials have been used extensively
in therapeutic drug delivery and medical implant device
applications. Sometimes, it is also desirable for such polymers to
be, not only biocompatible, but also biodegradable to obviate the
need for removing the polymer once its therapeutic value has been
exhausted.
[0005] Conventional methods of drug delivery, such as frequent
periodic dosing, are not ideal in many cases. For example, with
highly toxic drugs, frequent conventional dosing can result in high
initial drug levels at the time of dosing, often at near-toxic
levels, followed by low drug levels between doses that can be below
the level of their therapeutic value. However, with controlled drug
delivery, drug levels can be more nearly maintained at therapeutic,
but non-toxic, levels by controlled release in a predictable manner
over a longer term.
[0006] If a biodegradable medical device is intended for use as a
drug delivery or other controlled-release system, using a polymeric
carrier is one effective means to deliver the therapeutic agent
locally and in a controlled fashion, see Langer et al., "Chemical
and Physical Structures of Polymers as Carriers for Controlled
Release of Bioactive Agents", J. Macro Science, Rev. Macro Chem
Phys., C23(1), 61-126 (19833) As a result, less total drug is
required, and toxic side effects can be minimized. Polymers have
been used as carriers of therapeutic agents to effect a localized
and sustained release. See Leong et al., "Polymeric Controlled Drug
Delivery", Advanced Drug Delivery Reviews, 1:199-233(1987); Langer
et al., "New Methods of Drug Delivery", Science, 249:1527-33
(1990); and Chien et al., Novel Drug Delivery Systems (1982). Such
delivery systems offer the potential of enhanced therapeutic
efficacy and reduced overall toxicity.
[0007] For a non-biodegradable matrix, the steps leading to release
of the therapeutic agent are water diffusion into the matrix,
dissolution of the therapeutic agent, and diffusion of the
therapeutic agent out through the channels of the matrix. As a
consequence, the mean residence time of the therapeutic agent
existing in the soluble state is longer for a non-biodegradable
matrix than for a biodegradable matrix, for which passage through
the channels of the matrix, while it may occur, is no longer
required. Since many pharmaceuticals have short half-lives,
therapeutic agents can decompose or become inactivated within the
non-biodegradable matrix before they are released. This issue is
particularly significant for many bio-macromolecules and smaller
polypeptides, since these molecules are generally hydrolytically
unstable and have low permeability through a polymer matrix. In
fact, in a non-biodegradable matrix, many bio-macromolecules
aggregate and precipitate, blocking the channels necessary for
diffusion out of the carrier matrix.
[0008] These problems are alleviated by using a biodegradable
matrix that, in addition to some diffusional release, also allows
controlled release of the therapeutic agent by degradation of the
polymer matrix. Examples of classes of synthetic polymers that have
been studied as possible biodegradable materials include polyesters
(Pitt et al., "Biodegradable Drug Delivery Systems based on
Aliphatic Polyesters: Application to Contraceptives and Narcotic
Antagonists", Controlled Release of Bioactive Materials, 19-44
(Richard Baker et al. ed. 1980)); poly(amino acids) and
pseudo-poly(amino acids) (Pulapura et al., "Trends in the
Development of Bioresorbable Polymers for Medical Applications",
Journal of Biomaterials Applications, 6(1), 216-50 (1992));
polyurethanes (Bruin et al., "Biodegradable Lysine
Diisocyanate-based Poly(glycolide-co-.epsilon.-capr-
olactone)-urethane Network in Artificial Skin", Biomaterials,
11(4), 291-95 (1990)); polyorthoesters (Heller et al., "Release of
Norethindrone from Poly(OrthoEsters)", Polymer Engineering and
Science, 21(11), 727-31 (1981)); and polyanhydrides (Leong et al.,
"Polyanhydrides for Controlled Release of Bioactive Agents",
Biomaterials 7(5), 364-71 (1986)). Specific examples of
biodegradable materials that are used as medical implant materials
are polylactide, polyglycolide, polydioxanone,
poly(lactide-co-glycolide), poly(glycolide-co-polydioxanone),
polyanhydrides, poly(glycolide-co-trimethylene carbonate), and
poly(glycolide-co-caprolactone).
[0009] Polymers having phosphate linkages, called poly(phosphates),
poly(phosphonates) and poly(phosphites), are known. See Penczek et
al., "Phosphorus-Containing Polymers", Handbook of Polymer
Synthesis, Part B, Chapter 17, 1077-1132 (Hans R. Kricheldorf ed
1992). The respective structures of these three classes of
compounds, each having a different sidechain connected to the
phosphorus atom, are as follows: 2
[0010] The versatility of these polymers comes from the versatility
of the phosphorus atom, which is known for a multiplicity of
reactions. Its bonding can involve the 3p orbitals or various 3s-3p
hybrids; spd hybrids are also possible because of the accessible d
orbitals. Thus, the physico-chemical properties of the
poly(phosphoesters) can be readily changed by varying either the R
or R' group. The biodegradability of the polymer is due primarily
to the physiologically labile phosphoester bond in the backbone of
the polymer. By manipulating the backbone or the sidechain, a wide
range of biodegradation rates are attainable. Kadiyala et al.,
"Poly(phosphoesters): Synthesis, Physicochemical Characterization
and Biological Response", Biomedical Applications of Synthetic
Biodegradable Polymers, Chapter 3: 33-57 (Jeffrey O. Hollinger ed.,
1995).
[0011] An additional feature of poly(phosphoesters) is the
availability of functional side groups. Because phosphorus can be
pentavalent, drug molecules or other biologically active substances
can be chemically linked to the polymer. For example, drugs with
--O-carboxy groups may be coupled to the phosphorus via an ester
bond, which is hydrolyzable. The P--O--C group in the backbone also
lowers the glass transition temperature of the polymer and,
importantly, confers solubility in common organic solvents, which
is desirable for easy characterization and processing.
[0012] Friedman, U.S. Pat. No. 3,442,982, discloses a
poly(phosphoester-co-ester) polymer having, as its ester portion,
the following asymmetric group: 3
[0013] The polymers of Friedman are noted as being stable to
hydrolysis, heat and light. (Column 1, lines 42-44 and column 3,
lines 74-75).
[0014] Starck et al., Canadian Patent No. 597,473, disclose
poly(phosphonates), and the incorporation of the phosphorus is said
to make the resulting polymers incombustible. (Column 6, lines
1-2). Engelhardt et al., U.S. Pat. No. 5,530,093 discloses a
multitude of textile finishing compositions having a wide variety
of polycondensate structures with phosphoester and ester recurring
units. The ester portions of Starck et al. and Engelhardt et al.
are oriented as follows:
--O--CO--R.sub.3--CO--O--
[0015] There remains a need for materials such as the
poly(phosphoester-co-ester) compounds of the invention, which are
particularly well-suited for making biodegradable materials and
other biomedical applications.
SUMMARY OF THE INVENTION
[0016] The biodegradable polymers of the invention comprise the
recurring monomeric units shown in formula I or II: 4
[0017] wherein:
[0018] X is --O-- or --NR'--, where R' is H or alkyl;
[0019] M.sub.1 and M.sub.2 are each independently (1) a branched or
straight chain aliphatic group having from 1-20 carbon atoms; or
(2) a branched or straight chain, oxy-, carboxy- or amino-aliphatic
group having from 1-20 carbon atoms;
[0020] Y is --O--, --S-- or --NR'--;
[0021] L is a branched or straight chain aliphatic group having
from 1-20 carbon atoms;
[0022] R is H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or
heterocycloxy;
[0023] the molar ratio of x:y is about 1;
[0024] the molar ratio n:(x or y) is between about 200:1 and 1:200;
and
[0025] the molar ratio q:r is between about 1:99 and 99:1.
[0026] These biodegradable polymers are biocompatible before and
upon biodegradation.
[0027] In another embodiment, the invention comprises polymer
compositions comprising:
[0028] (a) at least one biologically active substance and
[0029] (b) a polymer having the recurring monomeric units shown in
formula I or II.
[0030] In yet another embodiment of the invention, an article
useful for implantation, injection, or otherwise being placed
totally or partially within the body, comprises the biodegradable
polymer of formula I or II or the above-described polymer
compositions.
[0031] In a further embodiment, the invention contemplates a
process for preparing a biodegradable polymer comprising the steps
of:
[0032] (a) reacting a heterocyclic ring compound having formula
III, IV, or V: 5
[0033] wherein
[0034] M.sub.1, M.sub.2 and X are as defined above, with an
initiator having the formula:
H--Y--L--Y--H,
[0035] wherein Y and L are as defined as above, to form a
prepolymer of formula VI or VII, shown below: 6
[0036] wherein X, M.sub.1, M.sub.2, Y. L, x, y, q and r are as
defined above; and
[0037] (b) further reacting said prepolymer of formula III, IV or V
with a phosphorodihalidate of formula VIII: 7
[0038] where "halo" is Br, Cl or I; and R is as defined above, to
form said polymer of formula VIII.
[0039] In another embodiment of the invention, a methods provided
for the controlled release of a biologically active substance
comprising the steps of:
[0040] (a) combining the biologically active substance with a
biodegradable polymer having the recurring monomeric units shown in
formula I or II to form an admixture;
[0041] (b) forming the admixture into a shaped, solid article;
and
[0042] (c) implanting or injecting the solid article in vivo at a
preselected site, such that the solid implanted or injected article
is in at least partial contact with a biological fluid.
BRIEF DESCRIPTION OF THE DRAWINGS
[0043] FIG. 1 shows the results of a GPC analysis of a polymer of
the invention in graphic form.
[0044] FIGS. 2A and 2B show differential scanning calorimetry data
for two polymers of the invention.
[0045] FIG. 3 shows the appearance of microspheres of a polymer of
the invention made by the solvent evaporation method.
[0046] FIGS. 4A and 4B show the weight loss (4A) and the change in
Mw (4B) for discs fabricated from two polymers of the invention
over a period of eight days in PBS at 37.degree. C.
[0047] FIG. 5 shows the change in Mw of two polymers of the
invention after being exposed to air at room temperature for one
month.
[0048] FIG. 6 shows the .sup.1H-NMR spectrum of a polymer of the
invention, P(LAEG-EOP).
[0049] FIG. 7 shows the .sup.31P-NMR spectrum of a polymer of the
invention, P(LAEG-EOP).
[0050] FIG. 8 shows shelf stability data for a polymer of the
invention at room temperature.
[0051] FIG. 9 shows cytotoxicity data for microspheres of a polymer
of the invention, P(LAEG-EOP).
[0052] FIGS. 10A and 10B show the weight loss (10A) and the change
in Mw (10B) for discs fabricated from two polymers of the
invention, in vitro.
[0053] FIGS. 11A and 11B show the weight loss (11A) and the change
in Mw (11B) for discs fabricated from the polymer of the invention,
in vivo.
[0054] FIG. 12 shows biocompatibility data for polymers of the
invention.
[0055] FIG. 13 shows the effect of fabrication method upon the
release rate of microspheres of a polymer of the invention.
[0056] FIG. 14 shows the rate of release of lidocaine and cisplatin
from microspheres of a polymer of the invention.
[0057] FIG. 15 shows the appearance of microspheres of a polymer of
the invention containing FITC-BSA.
[0058] FIG. 16 shows the rate of release of lidocaine from
microspheres of a polymer of the invention.
[0059] FIG. 17 shows the rate of release of lidocaine from
microspheres of a polymer of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0060] Polymers of the Invention
[0061] As used herein, the term "aliphatic" refers to a linear,
branched, cyclic alkane, alkene, or alkyne. Preferred aliphatic
groups in the poly(phosphoester-co-ester) polymer of the invention
are linear or branched and have from 1 to 10 carbons, preferably
being linear groups having from 1 to 7 carbon atoms.
[0062] As used herein, the term "aryl" refers to an unsaturated
cyclic carbon compound with 4n+2.times. electrons.
[0063] As used herein, the term "heterocyclic" refers to a
saturated or unsaturated ring compound having one or more atoms
other than carbon in the ring, for example, nitrogen, oxygen or
sulfur.
[0064] The biodegradable polymer of the invention comprises the
recurring monomeric units shown in formula I or II: 8
[0065] wherein x is --O-- or --NR'-- where R' is H or alkyl.
[0066] L can be any divalent branched or straight chain aliphatic
group having from 1-20 carbon atoms, so long as it does not
interfere with the polymerization or biodegradation reactions of
the polymer. Specifically, L can be an alkylene group, such as
methylene, ethylene, 1,2-dimethylethylene, n-propylene,
isopropylene, 2,2-dimethylpropylene or tert-butylene, n-pentylene,
tert-pentylene, n-hexylene, n-heptylene and the like; an alkylene
substituted with a non-interfering substituent, for example,
hydroxy-, halogen- or nitrogen-substituted alkylene; an alkenylene
group such as ethenylene, propenylene, 2-(3-propenyl)-dodecyle- ne;
and an alkynylene group such as ethynylene, proynylene,
1-(4-butynyl)-3-methyldecylene; and the like.
[0067] Preferably, however, L is independently a branched or
straight chain alkylene group, more preferably, an alkylene group
having from 1 to 7 carbon atoms. Even more preferably, L is an
ethylene group or a methyl-substituted methylene group and, most
preferably L is an ethylene group.
[0068] M.sub.1 and M.sub.2 in the formula are each independently
either (1) a branched or straight chain aliphatic group having from
1-20 carbon atoms or (2) a branched or straight chain, oxy-,
carboxy- or amino-aliphatic group having from 1-20 carbon atoms. In
either case the branched or straight chain aliphatic group can be
any divalent aliphatic moiety having from 1-20 carbon atoms,
preferably 1-7 carbon atoms, that 2' does not interfere with the
polymerization, copolymerization or biodegradation reactions of the
polymers. Specifically, when either M.sub.1 or M.sub.2 is a
branched or straight chain aliphatic group having from 1-20 carbon
atoms, it can be, for example, an alkylene group, such as
methylene, ethylene, 1-methylethylene, 1,2-dimethylethylene,
n-propylene, trimethylene, isopropylene, 2,2-dimethylpropylene,
tert-butylene, n-pentylene, tert-pentylene, n-hexylene,
n-heptylene, n-octylene, n-nonylene, n-decylene, n-undecylene,
n-dodecylene, and the like; an alkenylene group, such as
n-propenylene, 2-vinylpropylene, n-butenylene, 3-ethenylbutylene,
n-pentenylene, 4-(3-properyl)hexylene, n-octenylene,
1-(4-butenyl)-3-methyldecylene, 2-(3-propenyl)dodecylene,
hexadecenylene and the like; an alkynylene group, such as
ethynylene, propynylene, 3-(2-ethynyl)pentylene, n-hexynylene,
2-(2-propynyl)decylene, and the like; or an alkylene, alkenylene or
alkynylene group substituted with a non-interfering substituent,
for example, a hydroxy, halogen or nitrogen group, such as
2-chloro-n-decylene, 1-hydroxy-3-ethenylbutylene,
2-propyl-6-nitro-10-dod- ecynylene, and the like.
[0069] When either M.sub.1 or M.sub.2 is a branched or straight
chain, oxy-aliphatic group having from 1-20 carbon atoms, it can
be, for example, a divalent alkoxylene group, such as ethoxylene,
2-methylethoxylene, propoxylene, butoxylene, pentoxylene,
dodecyloxylene, hexadecyloxylene, and the like. When M.sub.1 or
M.sub.2 is a branched or straight chain, oxy-aliphatic group,
preferably, it has the formula --O--(CH.sub.2).sub.a-- where a is 1
to 7.
[0070] When either M.sub.1 or M.sub.2 is a branched or straight
chain, oxy-aliphatic group having from 1-20 carbon atoms, it can
also be, for example, a dioxyalkylene group such as dioxymethylene,
dioxyethylene, 1,3-dioxypropylene, 2-methoxy-1,3-dioxypropylene,
1,3-dioxy-2-methylpropy- lene, dioxy-n-pentylene,
dioxy-n-octadecylene, methoxylene-methoxylene,
ethoxylene-methoxylene, ethoxylene-ethoxylene,
ethoxylene-1-propoxylene, butoxylene-n-propoxylene,
pentadecyloxylene-methoxylene, and he like. When M.sub.1 or M.sub.2
is a branched or straight chain, dioxo-aliphatic group, preferably
it has the formula --O--(CH.sub.2).sub.a--O-- or
--O--(CH.sub.2).sub.a--O--(CH.sub.2).sub.b--, wherein each of a and
b is from 1 to 7.
[0071] When either M.sub.1 or M.sub.2 is a branched or straight
chain, carboxy-aliphatic group having from 1-20 carbon atoms, it
can also be, for example, a divalent carboxylic acid ester such as
the divalent radical of methyl formate, methyl acetate, ethyl
acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate,
ethyl propionate, allyl propionate, t-butyl acrylate, n-butyl
butyrate, vinyl chloroacetate, 2-methoxy-carbonylcyclohexanone,
2-acetoxycyclohexanone, and the like. When M.sub.1 or M.sub.2 is a
branched or straight chain, carboxy-aliphatic group, it preferably
has the formula --O--CHR.sup.2--CO--O--CHR.sup.3--, wherein R.sup.2
and R are each independently H, alkyl, alkoxy, aryl, aryloxy,
heterocyclic or heterocycloxy.
[0072] When either M.sub.1 or M.sub.2 is a branched or straight
chain, amino-aliphatic group having from 1-20 carbon atoms, it can
be a divalent amine such as --CH.sub.2NH--, --(CH.sub.2).sub.2N--,
--CH.sub.2(C.sub.2H,)N--, -n-C.sub.4H.sub.9NH--,
-t-C.sub.4H.sub.9NH--, --CH.sub.2(C.sub.3H,)N--,
--C.sub.2H,(C.sub.3H,)N--, --CH.sub.2(C.sub.8H.sub.17)N--, and the
like. When M.sub.1 or M.sub.2 is a branched or straight chain,
amino-aliphatic group, it preferably has the formula
--(CH.sub.2).sub.a--NR'-- where R' is H or lower alkyl.
[0073] Preferably, M.sub.1 and/or M.sub.2 is an alkylene group
having the formula --O--(CH.sub.2).sub.a-- where a is 1 to 7 and,
most preferably, is a divalent ethylene group. In a particularly
preferred embodiment, M.sub.1 and M.sub.2 are both present; M.sub.1
and M.sub.2 are not the same chemical entity; and M, and M.sub.2
are n-pentylene and the divalent radical of methyl acetate
respectively.
[0074] R in the polymer of the invention is H, alkyl, alkoxy, aryl,
aryloxy, heterocyclic or heterocycloxy residue.
[0075] Examples of useful alkyl R' groups include methyl, ethyl,
n-propyl, 1-propyl, n-butyl, tert-butyl, --C.sub.8H.sub.17, and the
like groups; alkyl substituted with a non-interfering substituent,
such as hydroxy, halogen, alkoxy or nitro; corresponding alkoxy
groups; and alkyl conjugated to a biologically active substance to
form a pendant drug delivery system.
[0076] When R is aryl or the corresponding aryloxy group, it
typically contains from about 5 to about 14 carbon atoms,
preferably about 5 to 12 carbon atoms and, optionally, can contain
one or more rings that are fused to each other. Examples of
particularly suitable aromatic groups include phenyl, phenoxy,
naphthyl, anthracenyl, phenanthrenyl and the like.
[0077] When R is heterocyclic or heterocycloxy, it typically
contains from about 5 to 14 ring atoms, preferably from about 5 to
12 ring atoms, and one or more heteroatoms. Examples of suitable
heterocyclic groups include furan, thiophene, pyrrole, isopyrrole,
3-isopyrrole, pyrazole, 2-isoimidazole, 1,2,3-triazole,
1,2,4-triazole, oxazole, thiazole, isothiazole, 1,2,3-oxadiazole,
1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3/4-oxadiazole,
1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, 1,2,3-dioxazole,
1,2,4-dioxazole, 1,3,2-dioxazole, 1,3,4-dioxazole,
1,2,5-oxatriazole, 1,3-oxathiole, 1,2-pyran, 1,4-pyran, 1,2-pyrone,
1,4-pyrone, 1,2-dioxin, 1,3-dioxin, pyridine, N-alkyl pyridinium,
pyridazine, pyrimidine, pyrazine, 1,3,5-triazine, 1,2,4-triazine,
1,2,3-triazine, 1,2,4-oxazine, 1,3,2-oxazine, 1,3,5-oxazine,
1,4-oxazine, o-isoxazine, p-isoxazine, 1,2,5-oxathiazine,
1,2,6-oxathiazine, 1,4,2-oxadiazine, 1,3,5,2-oxadiazine, azepine,
oxepin, thiepin, 1,2,4-diazepine, indene, isoindene, benzofuran,
isobenzofuran, thionaphthene, isothionaphthene, indole, indolenine,
2-isobenzazole, 1,4-pyrindine, pyrando[3,4-b]-pyrrole, isoindazole,
indoxazine, benzoxazole, anthranil, 1,2-benzopyran,
1,2-benzopyrone, 1,4-benzopyrone, 2,1-benzopyrone, 2,3-benzopyrone,
quinoline, isoquinoline, 12,-benzodiazine, 1,3-benzodiazine,
naphthyridine, pyrido[3,4-b]-pyridine, pyrido[3,2-b]-pyridine,
pyrido[4,3-b]pyridine, 1,3,2-benzoxazine, 1,4,2-benzoxazine,
2,3,1-benzoxazine, 3,1,4-benzoxazine, 1,2-benzisoxazine,
1,4-benzisoxazine, carbazole, xanthrene, acridine, purine, and the
like. Preferably, when R is heterocyclic or heterocycloxy, it is
selected from the group consisting of furan, pyridine,
N-alkylpyridine, 1,2,3- and 1,2,4-triazoles, indene, anthracene and
purine rings.
[0078] In a particularly preferred embodiment, R is an alkyl group,
an alkoxy group, a phenyl group, a phenoxy group, or a
heterocycloxy group and, even more preferably, an alkoxy group
having from 1 to 7 carbon atoms. Most preferably, R is an ethoxy
group.
[0079] The molar ratio of n:(x or y) can vary greatly depending on
the biodegradability and the release characteristics desired in the
polymer, but typically varies between about 200:1 and 1:200.
Preferably, the ratio x:y is from about 100:1 to about 1:100 and,
most preferably, from about 50:1 to about 1:50.
[0080] The molar ratio of q:r can vary greatly depending on the
biodegradability and the release characteristics desired in the
polymer, but typically varies between about 1:200 and 200:1.
Preferably, the ratio q:r is from about 1:150 to about 150:1 and,
most preferably, from about 1:99 to about 99:1.
[0081] The molar ratio of x:y can also vary greatly depending on
the biodegradability and the release characteristics desired in the
polymer but, typically, is about 1.
[0082] Biodegradable polymers differ from non-biodegradable
polymers in that they can be degraded during in vivo therapy. This
generally involves breaking down the polymer into its monomeric
subunits. In principle, the ultimate hydrolytic breakdown products
of a poly(phosphoester) are phosphate, alcohol, and diol, all of
which are potentially non-toxic. The intermediate oligomeric
products of the hydrolysis may have different properties, but the
toxicology of a biodegradable polymer intended for implantation or
injection, even one synthesized from apparently innocuous monomeric
structures, is typically determined after one or more in vitro
toxicity analyses. A typical toxicity assay would be performed with
live carcinoma cells, such as GT3TKB tumor cells, in the following
manner:
[0083] About 100-150 mg of the sample polymer is degraded in 20 mL
of 1M NaOH at 37.degree. C. for 1-2 days, or until complete
degradation is observed. The solution is then neutralized with 20
mL of 1M HCl. About 200 yL of various concentrations of the
degraded polymer products are placed in 96-well tissue culture
plates and seeded with human gastric carcinoma cells (GT3TKB) at
10.sup.4/well density. The degraded polymer products are incubated
with the GT3TKB cells for 48 hours. The results of the assay can be
plotted as % relative growth vs. concentration of degraded polymer
in the tissue-culture well.
[0084] The biodegradable polymer of the invention is preferably
sufficiently pure to be biocompatible itself and remains
biocompatible upon biodegradation. By "biocompatible" is meant that
the biodegradation products or the polymer itself are non-toxic and
result in only minimal tissue irritation when implanted or injected
into vasculated tissue.
[0085] The polymer of the invention is preferably soluble in one or
more common organic solvents for ease of fabrication as and
processing. Common organic solvents include such solvents as
chloroform, dichloromethane, acetone, ethyl acetate, DMAC, N-methyl
pyrrolidone, dimethylformamide, and dimethylsulfoxide. The polymer
is preferably soluble in at least one of the above solvents.
[0086] Synthesis of Poly(phosphoester-co-ester) Polymers
[0087] The most common general reaction in preparing
poly(phosphates) is a dehydrochlorination between a
phosphorodichloridate and a diol according to the following
equation: 9
[0088] Most poly(phosphonates) are also obtained by condensation
between appropriately substituted dichlorides and diols.
[0089] Poly(phosphites) have been prepared from glycols in a
two-step condensation reaction. A 20% molar excess of a
dimethylphosphite is used to react with the glycol, followed by the
removal of the methoxyphosphonyl end groups in the oligomers by
high temperature
[0090] An advantage of melt polycondensation is that it avoids the
use of solvents and large amounts of other additives, thus making
purification more straightforward. It can also provide polymers of
reasonably high molecular weight. Somewhat rigorous conditions,
however, are often required and can lead to chain acidolysis (or
hydrolysis if water is present). Unwanted, thermally-induced side
reactions, such as cross-linking reactions, can also occur if the
polymer backbone is susceptible to hydrogen atom abstraction or
oxidation with subsequent macroradical recombination.
[0091] To minimize these side reactions, the polymerization can
also be carried out in solution. Solution polycondensation requires
that both the prepolymer and the phosphorus component be soluble in
a common solvent. Typically, a chlorinated organic solvent is used,
such as chloroform, dichloromethane, or dichloroethane. The
solution polymerization must be run in the presence of equimolar
amounts of the reactants and a stoichiometric amount of an acid
acceptor, usually a tertiary amine such as pyridine or
triethylamine. The product is then typically isolated from the
solution by precipitation in a non-solvent and purified to remove
the hydrochloride salt by conventional techniques known to those of
ordinary skill in the art, such as by washing with an aqueous
acidic solution, e.g, dilute HCl.
[0092] Reaction times tend to be longer with solution
polymerization than with melt polymerization. However, because
overall milder reaction conditions can be used, side reactions are
minimized, and more sensitive functional groups can be incorporated
into the polymer. The disadvantages of solution polymerization are
that the attainment of high molecular weights, such as a Mw greater
than 20,000, is less likely.
[0093] Interfacial polycondensation can be used when high molecular
weight polymers are desired at high reaction rates. Mild conditions
minimize side reactions. Also the dependence of high molecular
weight on stoichiometric equivalence between diol and dichloridate
inherent in solution methods is removed. However, hydrolysis of the
acid chloride may occur in the alkaline aqueous phase. Sensitive
dichloridates that have some solubility in water are generally
subject to hydrolysis rather than polymerization. Phase transfer
catalysts, such as crown ethers or tertiary ammonium chloride, can
be used to bring the ionized diol to the interface to facilitate
the polycondensacion reaction. The yield and molecular weight of
the resulting polymer after interfacial polycondensation are
affected by reaction time, molar ratio of the monomers, volume
ratio of the immiscible solvents, the type of acid acceptor, and
the type and concentration of the phase transfer catalyst.
[0094] In a preferred embodiment of the invention, the
biodegradable polymer of formula I or II is made by a process
comprising the steps of:
[0095] (a) reacting at least one heterocyclic ring compound having
formula III, IV or V: 10
[0096] wherein
[0097] M.sub.1, M.sub.2 and X are as defined above, with an
initiator having the formula:
H--Y--L--Y--H,
[0098] wherein Y and L are as defined as above, to form a
prepolymer of formula VI or VII, shown below: 11
[0099] wherein X, MI, M.sub.2, Y, L, R, x, y, q and r are as
defined above; and
[0100] (b) further reacting said prepolymer of formula III, or IV
or V with a phosphorodihalidate of formula VIII 12
[0101] where "halo" is Br, Cl or I; and R is as defined above, to
form said polymer of formula I or I.
[0102] The function of the first reaction step (a) is to use the
initiator to open the ring of the heterocyclic ring compound of
formula III, IV or V. Examples of useful heterocyclic compounds of
formula III, IV or V include caprolactones, caprolactams, amino
acid anhydrides such as glycine anhydride, cycloalkylene
carbonates, dioxanones, glycolids, lactides and the like.
[0103] When the compound of the invention has formula I, only one
heterocyclic ring compound of formula III, which contains M, may be
used to prepare the prepolymer of formula VI in step (a) When the
compound of the invention has formula II, then a combination of a
heterocyclic compound of formula III, which contains M.sub.1, and a
heterocyclic compound of formula IV, which contains M.sub.2, may be
used in step (a) Alternatively, when the compound of the invention
has formula II, a single heterocyclic compound of formula V, which
contains both M, and M.sub.2' can be used in step (a).
[0104] Examples of suitable initiators include a wide variety of
compounds having at least two active hydrogens (H--Y--L--Y--H)
where L is a linking group and is defined above, and Y can be
--O--, --S-- or --NR", where RI is as defined above. The linking
group L is can be a straight chain group, e.g., alkylene, but it
may also be substituted with one or more additional
active-hydrogen-containing groups. For example, may a straight
chain alkylene grout substituted with one or more additional alkyl
groups, each bearing a activated hydrogen moiety, such as --OH,
--SH, or NT.sub.2. In this way, various branched polymers can be
prepared using the branched active hydrogen initiators to design
the resulting polymer such that it has the desired properties.
However, when branched polymers are reacted with acid chlorides,
cross-linked polymers will result.
[0105] The reaction step (a) can take place at widely varying
temperatures, depending upon the solvent used, the molecular weight
desired, the susceptibility of the reactants side reactions,
and-the presence of a catalyst. Prepared by, however, the reaction
step (a) takes place at a temperature from about 0 to about
+235.degree. C. for melt conditions. Somewhat lower temperatures
may be possible with the use of either a cationic or anionic
catalyst.
[0106] The time required for the reaction step (a) also can vary
widely, depending on the type of reaction being used and the
molecular weight desired. Preferably, however, the reaction step
(a) takes place during a time between about 1hour and 7 days.
[0107] While the reaction step (a) may be in bulk, in solution, by
interfacial polycondensation, or any other convenient method of
polymerization, preferably, the reaction step (a) takes place under
melt conditions.
[0108] Examples of particularly useful prepolymers of formula V
include:
[0109] (i) OH-terminated prepolymer derived from polycaprolactone
H--[--O(CH.sub.2).sub.5--CO--].sub.x--O--CH.sub.2--CH.sub.2--O--[--CO--(C-
H.sub.2).sub.5--C--].sub.y--H;
[0110] (ii) NH-terminated-prepolymer derived from polycaprolactam
(Nylon 6)
H--[--NH--(CH.sub.2).sub.5--CO--].sub.x--NH--CH.sub.2--CH.sub.2--NH--[-
--CO--(CH.sub.2).sub.5--NH--;
[0111] (iii) OH-terminated prepolymer derived from polylactide
H--[--OCH(CH.sub.3)--CO--].sub.x--O--CH.sub.2--CH.sub.2--O--[--CO--CH
(CH.sub.3)--O--].sub.y--H; and
[0112] (iv) OH-terminated prepolymer derived from polytrimethylene
carbonate H--[--O(CH.sub.2).sub.3--O--CO--
].sub.x--O--CH.sub.2--CH.sub.2-
--[--CO--O--(CH.sub.2).sub.3--O--].sub.y--H.
[0113] Examples of particularly useful prepolymers of fcrmula VI
include:
[0114] (i) OH-terminated copolymer derived from lactide and
glycolide: 13
[0115] (ii) OH-terminated copolymer derived from lactide and
caprolactone: 14
[0116] and
[0117] (iii) OH-terminated copolymer derived from glycolide and
caprolactone: 15
[0118] The purpose of the polymerization of step (b) is to form a
polymer comprising (i) the prepolymer produced as a result of step
(a) and (ii) interconnecting phosphorylated units. The result can
be a block copolymer having a microcrystalline structure that is
particularly well-suited to use as a controlled release medium.
[0119] The polymerization step (b) of the invention usually takes
place at a slightly lower temperature than the temperature of step
(a),- but also may vary widely, depending upon the type of
polymerization reaction used, the presence of one or more
catalysts, the molecular weight desired, and the susceptibility of
the reactants to undesirable side reaction. When melt conditions
are used, the temperature may vary from about 0-150.degree. C.
However, when the polymerization step (b) is carried out in a
solution polymerization reaction, it typically takes place at a
temperature between about -40 and 100.degree. C. Typical solvents
include methylene chloride, chloroform, or any of a wide variety of
inert organic solvents.
[0120] The time required for the polymerization of step (b) can
also vary widely, depending on the molecular weight of the material
desired and, in general, the need to use more or less rigorous
conditions for the reaction to proceed to the desired degree of
completion. Typically, however, the polymerization step (b) takes
place during a time of about 30 minutes to 48 hours.
[0121] Particularly when solution polymerization reaction is used,
an acid acceptor is advantageously present during the
polymerization step (a). A particularly suitable class of acid
acceptor comprises tertiary amines, such as pyridine,
trimethylamine, triethylamine, substituted anilines and substituted
aminopyridines. The most preferred acid acceptor is the substituted
aminopyridine 4-dimethylaminopyridine ("DMAP").
[0122] The polymers of formula I and II are isolated from the
reaction mixture by conventional techniques, such as by
precipitating out, extraction with an immiscible solvent,
evaporation, filtration, crystallization and the like. Typically,
however, the polymers of formulas I and II are both isolated and
purified by quenching a solution of said polymer with a non-solvent
or a partial solvent, such as diethyl ether or petroleum ether.
[0123] Biodegradability and Release Characteristics
[0124] The polymers of formulas I and II are usually characterized
by a release rate of the biologically active substance in vivo that
is controlled at least in part as a function of hydrolysis of the
phosphoester bond of the polymer during biodegradation.
Additionally, the biologically active substance to be released may
be conjugated to the phosphorus sidechain A' to form a pendant drug
delivery system. Further, other factors are also important.
[0125] The life of a biodegradable polymer in vivo also depends
upon its molecular weight, crystallinity, biostability, and the
degree of cross-linking. In general, the greater the molecular
weight, the higher the degree of crystallinity, and the greater the
biostability, the slower biodegradation will be.
[0126] Accordingly, the structure of the sidechain can influence
the release behavior of compositions comprising a biologically
active substance. For example, it is expected that conversion of
the phosphate sidechain to a more lipophilic, more hydrophobic or
bulky group would slow down the degradation process. Thus, release
is usually faster from polymer compositions with a small aliphatic
group sidechain than with a bulky aromatic sidechain.
[0127] Polymer Compositions
[0128] The polymers of formulas I and II can be used either alone
or as a composition containing, in addition, a biologically active
substance to form a variety of useful biodegradable materials. For
example, the polymers of formulas I and II can be used to produce a
biosorbable suture, an orthopedic appliance or bone cement for
repairing injuries to bone or connective tissue, a laminate for
degradable or non-degradable fabrics, or a coating for an
implantable device, even without the presence of a biologically
active substance.
[0129] Preferably, however, the biodegradable polymer composition
comprises both:
[0130] (a) at least one biologically active substance and
[0131] (b) the polymer having the recurring monomeric units shown
in formula I or II where X, M.sub.1, M.sub.2, L, R, Y, x, y, q, r
and n are as defined above.
[0132] The biologically active substance of the invention can vary
widely with the purpose for the composition. The active
substance(s) may be described as a single entity or a combination
of entities. The delivery system is designed to be used with
biologically active substances having high water-solubility as well
as with those having low water-solubility to produce a delivery
system that has controlled release rates. The term "biologically
active substance" includes without limitation, medicaments;
vitamins; mineral supplements; substances used for the treatment,
prevention, diagnosis, cure or mitigation of disease or illness; or
substances which affect the structure or function of the body; or
pro-drugs, which become biologically active or more active after
they have been placed in a predetermined physiological
environment.
[0133] Non-limiting examples of broad categories of useful
biologically active substances include the following expanded
therapeutic categories: anabolic agents, antacids, anti-asthmatic
agents, anti-cholesterolemic and anti-lipid agents,
anti-coagulants, anti-convulsants, anti-diarrheals, anti-emetics,
anti-infective agents, anti-inflammatory agents, anti-manic agents,
anti-nauseants, anti-neoplastic agents, anti-obesity agents,
anti-pyretic and analgesic agents, anti-spasmodic agents,
anti-thrombotic agents, anti-uricemic agents, anti-anginal agents,
antihistamines, anti-tussives, appetite suppressants, biologicals,
cerebral dilators, coronary dilators, decongestants, diuretics,
diagnostic agents, erythropoietic agents, expectorants,
gastrointestinal sedatives, hyperglycemic agents, hypnotics,
hypoglycemic agents, ion exchange resins, laxatives, mineral
supplements, mucolytic agents, neuromuscular drugs, peripheral
vasodilators, psychotropics, sedatives, stimulants, thyroid and
anti-thyroid agents, uterine relaxants, vitamins, and prodrugs.
[0134] Specific examples of useful biologically active substances
from the above categories include: (a) anti-neoplastics such as
androgen inhibitors, antimetabolites, cytotoxic agents,
immunomodulators; (b) anti-tussives such as dextromethorphan,
dextromethorphan hydrobromide, noscapine, carbetapentane citrate,
and chlorphedianol hydrochloride; (c) antihistamines such as
chlorpheniramine maleate, phenindamine tartrate, pyrilamine
maleate, doxylamine succinate, and phenyltoloxamine citrate; (d)
decongestants such as phenylephrine hydrochloride,
phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride,
and ephedrine; (e) various alkaloids such as codeine phosphate,
codeine sulfate and morphine; (f) mineral supplements such as
potassium chloride, zinc chloride, calcium carbonates, magnesium
oxide, and other alkali metal and alkaline earth metal salts; (9)
ion exchange resins such as cholestyramine; (h) anti-arrhythmics
such as N-acetylprocainamide; (i) antipyretics and analgesics such
as acetaminophen, aspirin and ibuprofen; (j) appetite suppressants
such as phenyl-propanolamine hydrochloride or caffeine; (k)
expectorants such as guaifenesin; (1) antacids such as aluminum
hydroxide and magnesium hydroxide; (m) biologicals such as
peptides, polypeptides, proteins and amino acids, hormones,
interferons or cytokines and other bioactive pepcidic compounds,
such as hGH, tPA, calcitonin, ANF, EPO and insulin; and (n)
anti-infective agents such as anti-fungals, anti-virals,
antiseptics and antibiotics.
[0135] Preferably, the biologically active substance is selected
from the group consisting of polysaccharides, growth factors,
hormones, anti-angiogenesis factors, interferons or cytokines, and
pro-drugs. More specifically, non-limiting examples of useful
biologically active substances include the following therapeutic
categories: analgesics, such as nonsteroidal anti-inflammatory
drugs, opiate agonists and salicylates; antihistamines, such as
H.sub.1-blockers and H.sub.2-blockers; anti-infective agents, such
as antihelmintics, antianaerobics, antibiotics, aminoglycoside
antibiotics, antifungal antibiotics, cephalosporin antibiotics,
macrolide antibiotics, miscellaneous .beta.-lactam antibiotics,
penicillin antibiotics, quinolone antibiotics, sulfonamide
antibiotics, tetracycline antibiotics, antimycobacterials,
antituberculosis antimycobacterials, antiprotozoals, antimalarial
antiprotozoals, antiviral agents, anti-retroviral agents,
scabicides, and urinary anti-infectives; antineoplastic agents,
such as alkylating agents, nitrogen mustard alkylating agents,
nitrosourea alkylating agents, antimetabolites, purine analog
antimetabolites, pyrimidine analog antimetabolites, hormonal
antineoplastics, natural antineoplastics, antibiotic natural
antineoplastics, and vinca alkaloid natural antineoplastics;
autonomic agents, such as anticholinergics, antimuscarinic
anticholinergics, ergot alkaloids, parasympathomimetics,
cholinergic agonist parasympathomimetics, cholinesterase inhibitor
parasympathomimetics, sympatholytics, .alpha.-blocker
sympatholytics, .beta.-blocker sympatholytics, sympathomimetics,
and adrenergic agonist sympathomimetics; cardiovascular agents,
such as antianginals, .beta.-blocker antianginals, calcium-channel
blocker antianginals, nitrate antianginals, antiarrhythmics,
cardiac glycoside antiarrhythmics, class I antiarrhythmics, class
II antiarrhythmics, class III antiarrhythmics, class IV
antiarrhythmics, antihypertensive agents, .alpha.-blocker
antihypertensives, angiotensin-converting enzyme inhibitor (ACE
inhibitor) antihypertensives, .beta.-blocker antihypertensives,
calcium-channel blocker antihypertensives, central-acting
adrenergic anti-hypertensives, diuretic antihypertensive agents,
peripheral vasodilator antihypertensives, antilipemics, bile acid
sequestrant antilipemics, HMG-COA reductase inhibitor
antilipemics,-inotropes, cardiac glycoside inotropes, and
thrombolytic agents; dermatological agents, such as antihistamines,
anti-inflammatory agents, corticosteroid anti-inflammatory agents,
antipruritics/local anesthetics, topical anti-infectives,
antifungal topical anti-infectives, antiviral topical
anti-infectives, and topical anti-neoplastics; electrolytic and
renal agents, such as acidifying agents, alkalinizing agents,
diuretics, carbonic anhydrase inhibitor diuretics, loop diuretics,
osmotic diuretics, potassium-sparing diuretics, thiazide diuretics,
electrolyte replacements, and uricosuric agents; enzymes, such as
pancreatic enzymes and thrombolytic enzymes; gastrointestinal
agents, such as antidiarrheals, anti-emetics, gastrointestinal
anti-inflammatory agents, salicylate gastrointestinal
anti-inflammatory agents, antacid anti-ulcer agents, gastric
acid-pump inhibitor anti-ulcer agents, gastric mucosal anti-ulcer
agents, H.sub.2-blocker anti-ulcer agents, cholelitholytic agents,
digestants, emetics, laxatives and stool softeners, and prokinetic
agents; general anesthetics, such as inhalation anesthetics,
halogenated inhalation anesthetics, intravenous anesthetics,
barbiturate intravenous anesthetics, benzodiazepine intravenous
anesthetics, and opiate agonist intravenous anesthetics;
hematological agents, such as antianemia agents, hematopoietic
antianemia agents, coagulation agents, anticoagulants, hemostatic
coagulation agents, platelet inhibitor coagulation agents,
thrombolytic enzyme coagulation agents, and plasma volume
expanders; hormones and hormone modifiers, such as abortifacients,
adrenal agents, corticosteroid adrenal agents, androgens,
anti-androgens, antidiabetic agents, sulfonylurea antidiabetic
agents, antihypoglycemic agents, oral contraceptives, progestin
contraceptives, estrogens, fertility agents, oxytocics, parathyroid
agents, pituitary hormones, progestins, antithyroid agents, thyroid
hormones, and tocolytics; immunobiologic agents, such as
immunoglobulins, immunosuppressives, toxoids, and vaccines; local
anesthetics, such as amide local anesthetics and ester local
anesthetics; musculoskeletal agents, such as anti-gout
anti-inflammatory agents, corticosteroid anti-inflammatory agents,
gold compound anti-inflammatory agents, immunosuppressive
anti-inflammatory agents, nonsteroidal anti-inflammatory drugs
(NSAIDs), salicylate anti-inflammatory agents, skeletal muscle
relaxants, neuro-muscular blocker skeletal muscle relaxants, and
reverse neuromuscular blocker skeletal muscle relaxants;
neurological agents, such as anticonvulsants, barbiturate
anticonvulsants, benzodiazepine anticonvulsants, anti-migraine
agents, anti-parkinsonian agents, anti-vertigo agents, opiate
agonists, and opiate antagonists; ophthalmic agents, such as
anti-glaucoma agents, .beta.-blocker anti-glaucoma agents, miotic
anti-glaucoma agents, mydriatics, adrenergic agonist mydriatics,
antimuscarinic mydriatics, ophthalmic anesthetics, ophthalmic
anti-infectives, ophthalmic aminoglycoside anti-infectives,
ophthalmic macrolide anti-infectives, ophthalmic quinolone
anti-infectives, ophthalmic sulfonamide anti-infectives, ophthalmic
tetracycline anti-infectives, ophthalmic anti-inflammatory agents,
ophthalmic corticosteroid anti-inflammatory agents, and ophthalmic
nonsceroidal anti-inflammatory drugs (NSAIDs); psychotropic agents,
such as antidepressants, heterocyclic antidepressants, monoamine
oxidase inhibitors (MAOIs), selective serotonin re-uptake
inhibitors (SSRIs), tricyclic antidepressants, antimanics,
antipsychotics, phenothiazine antipsychotics, anxiolytics,
sedatives, and hypnotics, barbiturate sedatives and hypnotics,
benzodiazepine anxiolytics, sedatives, and hypnotics, and
psychostimulants; respiratory agents, such as antitussives,
bronchodilators, adrenergic agonist bronchodilators, antimuscarinic
bronchodilators, expectorants, mucolytic agents, respiratory
anti-inflammatory agents, and respiratory corticosteroid
anti-inflammatory agents; toxicology agents, such as antidotes,
heavy metal antagonists/chelating agents, substance abuse agents,
deterrent substance abuse agents, and withdrawal substance abuse
agents; minerals; and vitamins, such as vitamin A, vitamin B,
vitamin C, vitamin D, vitamin E, and vitamin K.
[0136] Preferred classes of useful biologically active substances
from the above categories include: (1) nonsteroidal
anti-inflammatory drugs (NSAIDs) analgesics, such as diclofenac,
ibuprofen, ketoprofen, and naproxen; (2) opiate agonist analgesics,
such as codeine, fentanyl, hydromorphone, and morphine; (3)
salicylate analgesics, such as aspirin (ASA) (enteric coated ASA);
(4) H,-blocker antihistamines, such as clemastine and terfenadine;
(5) H.sub.2-blocker antihistamines, such as cimetidine, famotidine,
nizadine, and ranitidine; (6) anti-infective agents, such as
mupirocin; (7) antianaerobic anti-infectives, such as
chloramphenicol and clindamycin; (8) antifungal antibiotic
anti-infectives, such as amphotericin b, clotrimazole, fluconazole,
and ketoconazole; (9) macrolide antibiotic anti-infectives, such as
azithromycin and erythromycin; (10) miscellaneous .beta.-lactam
antibiotic anti-infectives, such as aztreonam and imipenem; (11)
penicillin antibiotic anti-infectives, such as nafcillin,
oxacillin, penicillin G. and penicillin V; (12) quinolone
antibiotic anti-infectives, such as ciprofloxacin and norfloxacin;
(13) tetracycline antibiotic anti-infectives, such as doxycycline,
minocycline, and tetracycline; (14) antituberculosis
antimycobacterial anti-infectives such as isoniazid (INH), and
rifampin; (1S) antiprotozoal anti-infectives, such as atovaquone
and dapsone; (16) antimalarial antiprotozoal anti-infectives, such
as chloroquine and pyrimethamine; (17) anti-retroviral
anti-infectives, such as ritonavir and zidovudine; (18) antiviral
anti-infective agents, such as acyclovir, ganciclovir, interferon
alfa, and rimantadine; (19) alkylating antineoplastic agents, such
as carboplatin and cisplatin; (20) nitrosourea alkylating
antineoplastic agents, such as carmustine (BCNU); (21)
antimetabolite antineoplastic agents, such as methotrexate; (22)
pyrimidine analog antimetabolite antineoplastic agents, such as
fluorouracil (5-FU) and gemcitabine; (23) hormonal antineoplastics,
such as goserelin, leuprolide, and tamoxifen; (24) natural
antineoplastics, such as aldesleukin, interleukin-2, docetaxel,
eroposide (VP-16), interferon alfa, paclitaxel, and tretinoin
(ATRA); (25) antibiotic natural antineoplastics, such as bleomycin,
dactinomycin, daunorubicin, doxorubicin, and mitomycin; (26) vinca
alkaloid natural antineoplastics, such as vinblastine and
vincristine; (27) autonomic agents, such as nicotine; (28)
anticholinergic autonomic agents, such as benztropine and
trihexyphenidyl; (29) antimuscarinic anticholinergic autonomic
agents, such as atropine and oxybutynin; (30) ergot alkaloid
autonomic agents, such as bromocriptine; (31) cholinergic agonist
parasympathomimetics, such as pilocarpine; (32) cholinesterase
inhibitor parasympathomimetics, such as pvridostigmine; (33)
.alpha.-bloclcer sympatholytics, such as prazosin; (34)
.beta.-blocker sympatholytics, such as atenolol; (35) adrenergic
agonist sympathomimetics, such as albuterol and dobutamine; (36)
cardiovascular agents, such as aspirin (ASA) (enteric coated ASA);
(37) .beta.-blocker antianginals, such as atenolol and propranolol;
(38) calcium-channel blocker antianginals, such as nifedipine and
verapamil; (39) nitrate antianginals, such as isosorbide dinitrate
(ISDN); (40) cardiac glycoside antiarrhythmics, such as digoxin;
(41) class I antiarrhythmics, such as lidocaine, mexiletine,
phenytoin, procainamide, and quinidine; (42) class II
antiarrhythmics, such as atenolol, metoprolol, propranolol, and
timolol; (43) class III antiarrhythmics, such as amiodarone; (44)
class IV antiarrhythmics, such as diltiazem and verapamil; (45)
.alpha.-blocker antihypertensives, such as prazosin; (46)
angiotensin-converting enzyme inhibitor (ACE inhibitor)
antihypertensives, such as captopril and enalapril; (47)
.beta.-blocker antihypertensives, such as atenolol, metoprolol,
nadolol, and propranolol; (48) calcium-channel blocker
antihypertensive agents, such as diltiazem and nifedipine; (49)
central-acting adrenergic antihypertensives, such as clonidine and
methyldopa; (50) diuretic antihypertensive agents, such as
amiloride, furosemide, hydrochlorothiazide (HCTZ), and
spironolactone; (51) peripheral vasodilator ancihypertensives, such
as hydralazine and minoxidil; (52) antilipemics, such as
gemfibrozil and Drobucol; (53) blue acid sequestrant antilipemics,
such as cholestyramine; (54) HMG-CoA reductase inhibitor
antilipemics, such as lovastatin and pravastatin; (55) inotropes,
such as amrinone, dobutamine, and dopamine; (56) cardiac glycoside
inotropes, such as digoxin; (57) thrombolytic agents, such as
alteplase (TPA), anistreplase, streptokinase, and urokinase; (58)
dermatological agents, such as colchicine, isotretlinoin,
methotrexate, minoxidil, tretinoin (ATRA); (59) dermatological
corticosteroid anti-inflammatory agents, such as betamethasone and
dexamethasone; (60) antifungal topical anti-infectives, such as
amohotericin 9, clotrimazole, miconazole, and nystatin; (61)
antiviral topical anti-infectives, such as acyclovir; (62) topical
antineoplastics, such as fluorouracil (5-FU); (63) electrolytic and
renal agents, such as lactulose; (64) loop diuretics, such as
furosemide; (65) potassium-sparing diuretics, such as triamterene;
(66) thiazide diuretics, such as hydrochlorothiazide (HCTZ); (67)
uricosuric agents, such as probenecid; (68) enzymes such as RNase
and DNase; (69) thrombolytic enzymes, such as alteplase,
anistreplase, streptokinase and urokinase; (70) antiemetics, such
as prochlorperazine; (71) salicylate gastrointestinal
anti-inflammatory agents, such as sulfasalazine; (72) gastric
acid-pump inhibitor anti-ulcer agents, such as omeprazole; (73)
H.sub.2-blocker anti-ulcer agents, such as cimetidine, Is
famotidine, nizatidine, and ranitidine; (74) digestants, such as
pancrelipase; (75) prokinetic agents, such as erythromycin; (76)
opiate agonist intravenous anesthetics such as fentanyl; (77)
hematopoietic antianemia agents, such as erythropoietin, filgrastim
(G-CSF), and sargramostim (GM-CSF); (78) coagulation agents, such
as antihemophilic factors 1-10 (AHF 1-10); (79) anticoagulants,
such as warfarin; (80) thrombolytic enzyme coagulation agents, such
as alteplase, anistreplase, streptokinase and urokinase; (81)
hormones and hormone modifiers, such as bromocriptine; (82)
abortifacients, such as methotrexate; (83) and antidiabetic agents,
such as insulin; (84) oral contraceptives, such as estrogen and
progestin; (85) progestin contraceptives, such as levonorgestrel
and norgestrel; (86) estrogens such as conjugated estrogens,
diethylstilbestrol (DES), estrogen (estradiol, estrone, and
estropipate); (87) fertility agents, such as clomiphene, human
chorionic gonadotropin (HCG), and menotropins; (88) parathyroid
agents such as calcitonin; (89) pituitary hormones, such as
desmopressin, goserelin, oxytocin, and vasopressin (ADH); (90)
progestins, such as medroxyprogesterone, norethindrone, and
progesterone; (91) thyroid hormones, such as levothyroxine; (92)
immunobiologic agents, such as interferon beta-1b and interferon
gamma-1b; (93) immunoglobulins, such as immune globulin IM, IMIG,
IGIM and immune globulin IV, IVIG, IGIV; (94) amide local
anesthetics, such as lidocaine; (95) ester local anesthetics, such
as benzocaine and procaine; (96) musculoskeletal corticosteroid
anti-inflammatory agents, such as beclomethasone, betamethasone,
cortisone, dexamethasone, hydrocortisone, and prednisone; (97)
musculoskeletal anti-inflammatory immunosuppressives, such as
azathioprine, cyclophosphamide, and methotrexate; (98)
musculoskeletal nonsteroidal anti-inflammatory drugs (NSAIDs), such
as diclofenac, ibuprofen, ketoprofen, ketorlac, and naproxen; (99)
skeletal muscle relaxants, such as baclofen, cyclobenzaprine, and
diazepam; (100) reverse neuromuscular blocker skeletal muscle
relaxants, such as pyridostigmine; (101) neurological agents, such
as nimodipine, riluzole, tacrine and ticlopidine; (102)
anticonvulsants, such as carbamazepine, gabapentin, lamotrigine,
phenytoin, and valproic acid; (103) barbiturate anticonvulsants,
such as phenobarbital and primidone; (104) benzodiazepine
anticonvulsants, such as clonazepam, diazepam, and lorazepam; (105)
anti-parkinsonian agents, such as bromocriptine, levodopa,
carbidopa, and pergolide; (106) anti-vertigo agents, such as
meclizine; (107) opiate agonists, such as codeine, fentanyl,
hydromorphone, methadone, and morphine; (108) opiate antagonistis,
such as aloxone; (109) 6-blocker anti-glaucoma agents, such as
t-imolol; (110) miotic anti-glaucoma agents, such as pilocarpine;
(111) ophthalmic aminoglycoside anti-infectives, such as
gentamicin, neomycin, and tobramycin; (112) ophthalmic quinolone
anti-infectives, such as ciprofloxacin, norfloxacin, and ofloxacin;
(113) ophthalmic corticosteroid anti-inflammatory agents, such as
dexamethasone and prednisolone; (114) ophthalmic nonsteroidal
anti-inflammatory drugs (NSAIDs), such as diclofenac; (115)
antipsychotics, such as clozapine, haloperidol, and risperidone;
(116) benzodiazepine anxiolytics, sedatives and hypnotics, such as
clonazepam, diazepam, lorazepam, oxazepam, and prazepam; (117)
psychostimulants,-such-asmethylphenidate and pemoline; (118)
antitussives, such as codeine; (119) bronchodilators, such as
theophylline; (120) adrenergic agonist bronchodilators, such as
albuterol; (121) respiratory corticosteroid anti-inflammatory
agents, such as dexamethasone; (122) antidotes, such as flumazenil
and naloxone; (123) heavy metal antagonists/chelating agents, such
as penicillamine; (124) deterrent substance abuse agents, such as
disulfiram, naltrexone, and nicotine; (125) withdrawal substance
abuse agents, such as bromocriptine; (126) minerals, such as iron,
calcium, and magnesium; (127) vitamin B compounds, such as
cyanocobalamin (vitamin B.sub.12) and niacin (vitamin Be); (128)
vitamin C compounds, such as 1S ascorbic acid; and (129) vitamin D
compounds, such as calcitriol.
[0137] In addition to the foregoing, the following less common
drugs may also be used: chlorhexidine; estradiol cypionate in oil;
estradiol valerate in oil; flurbiprofen; flurbiprofen sodium;
ivermectin; levodopa; nafarelin; and somatropin.
[0138] Further, the following new drugs may also be used:
recombinant beta-glucan; bovine immunoglobulin concentrate; bovine
superoxide dismutase; the formulation comprising fluorouracil,
epinephrine, and bovine collagen; recombinant hirudin (r-Hir HIV-1
immunogen; human anti-TAC antibody; recombinant human growth
hormone (r-hGH); recombinant human hemoglobin (r-Hb); recombinant
human mecasermin (r-IGF-1); recombinant interferon beta-la;
lenograstim (G-CSF); olanzapine; recombinant thyroid stimulating
hormone (r-TSH); and topotecan.
[0139] Further still, the following intravenous products may be
used: acyclovir sodium; aldesleukin; atenolol; bleomycin sulfate,
human calcitonin; salmon calcitonin; carboplatin; carmustine;
dactinomycin, daunorubicin HCl; docetaxel; doxorubicin HCl; epoetin
alfa; etoposide (VP-16); fluorouracil (5-FU); ganciclovir sodium;
gentamicin sulfate; interferon alfa; leuprolide acetate; meperidine
HCl; methadone HCl; methotrexate sodium; paclitaxel; ranitidine
HCl; vinblastin sulfate; and zidovudine (AZT).
[0140] Still further, the following listing of peptides, proteins,
and other large molecules may also be used, such as interleukins 1
through 18, including mutants and analogues; interferons .alpha.,
.beta., and .gamma.; luteinizing hormone releasing hormone (LHRH)
and analogues, gonadotropin releasing hormone (GnRH), transforming
growth factor-.beta. (TGF-.beta.); fibroblast growth factor (FGF);
tumor necrosis factor-.alpha. & .beta. (TNF-.alpha. &
.beta.) nerve growth factor (NGF); growth hormone releasing factor
(GHRF); epidermal growth factor (EGF); fibroblast growth factor
homologous factor (FGFHF); hepatocyte growth factor (HGF); insulin
growth factor (IGF); invasion inhibiting factor-2 (IIF-2); bone
morphogenetic proteins 1-7 (BMP 1-7); somatostatin;
thymosin-.alpha.-1; .gamma.-globulin; superoxide dismutase (SOD);
and complement factors.
[0141] Alternatively, the biologically active substance may be a
radiosensitizer, such as metoclopramide, sensamide or neusensamide
(manufactured by Oxigene); profiromycin (made by Vion); RSR13 (made
by Allos); Thymitaq (made by Agouron), etanidazole or lobenguane
(manufactured by Nycomed); gadolinium texaphrin (made by
Pharmacyclics); BuDR/Broxine (made by NeoPharm); IPdR (made by
Sparta); CR2412 (made by Cell Therapeutic); LlX (made by Terrapin);
or the like.
[0142] In a particularly preferred embodiment, the biologically
active substance is a therapeutic drug or pro-drug, most preferably
a drug selected from the group consisting of chemotherapeutic
agents and other anti-neoplastics, antibiotics, anti-virals,
anti-fungals, anti-inflammatories, and anticoagulants. Most
preferably, the biologically active substance is paclitaxel.
[0143] The biologically active substances are used in amounts that
are therapeutically effective. While the effective amount of a
biologically active substance will depend on the particular
material being used, amounts of the biologically active substance
from about 11 to about 65 have been easily incorporated into the
present delivery systems while achieving controlled release. Lesser
amounts may be used to achieve efficacious levels of treatment for
certain biologically active substances.
[0144] Pharmaceutically acceptable carriers may be prepared from a
wide range of materials. Without being limited thereto, such
materials include diluents, binders and adhesives, lubricants,
disintegrants, colorants, bulking agents, flavorings, sweeteners
and miscellaneous materials such as buffers and adsorbents in order
to prepare a particular medicated composition.
[0145] Implants and Delivery Systems Designed for Injection
[0146] In its simplest form, a biodegradable therapeutic agent
delivery system consists of a dispersion of the therapeutic agent
in a polymer matrix. The therapeutic agent is typically released as
the polymeric matrix biodegrades in vivo into soluble products that
can be excreted from the body.
[0147] In a particularly preferred embodiment, an article is used
for implantation, injection, or otherwise placed totally or
partially within the body, the article comprising the biodegradable
polymer composition of the invention. The biologically active
substance of the composition and the polymer of the invention may
form a homogeneous matrix, or the biologically active substance may
be encapsulated in some way within the polymer. For example, the
biologically active substance may be first encapsulated in a
microsphere and then combined with the polymer in such a way that
at least a portion of the microsphere structure is maintained.
[0148] Alternatively, the biologically active substance may be
sufficiently immiscible in the polymer of the invention that it is
dispersed as small droplets, rather than being dissolved, in the
polymer. Either form is acceptable, but it is preferred that,
regardless of the homogeneity of the composition, the release rate
of the biologically active substance in vivo remain controlled, at
least partially as a function of hydrolysis of the phosphoester
bond of the polymer upon biodegradation.
[0149] In a preferred embodiment, the article of the invention is
designed for implantation or injection into the body of an animal.
It is particularly important that such an article result in minimal
tissue irritation when implanted or injected into vasculated
tissue.
[0150] As a structural medical device, the polymer compositions of
the invention provide a physical form having specific chemical,
physical, and mechanical properties sufficient for the application
and a composition that degrades in vivo into non-toxic residues.
Typical structural medical articles include such implants as
orthopedic fixation devices, ventricular shunts, laminates for
degradable fabric, drug-carriers, biosorbable sutures, burn
dressings, coatings to be placed on other implant devices, and the
like.
[0151] In orthopedic articles, the composition of the invention may
be useful for repairing bone and connective tissue injuries. For
example, a biodegradable porous material can be loaded with bone
morphogenetic proteins to form a bone graft useful for even large
segmental defects. In vascular graft applications, a biodegradable
material in the form of woven fabric can be used to promote tissue
ingrowth. The polymer composition of the invention may be used as a
temporary barrier for preventing tissue adhesion, e.g., following
abdominal surgery.
[0152] On the other hand, in nerve regeneration articles, the
presence of a biodegradable supporting matrix can be used to
facilitate cell adhesion and proliferation. When the polymer
composition is fabricated as a tube for nerve generation, for
example, the tubular article can also serve as a geometric guide
for axonal elongation in the direction of functional recovery.
[0153] As a drug delivery device, the polymer compositions of the
invention provide a polymeric matrix capable of sequestering a
biologically active substance and provide predictable, controlled
delivery of the substance. The polymeric matrix then degrades to
non-toxic residues.
[0154] Biodegradable medical implant devices and drug delivery
products can be prepared in several ways. The polymer can be melt
processed using conventional extrusion or injection molding
techniques, or these products can be prepared by dissolving in an
appropriate solvent, followed by formation of the device, and
subsequent removal of the solvent by evaporation or extraction.
[0155] Once a medical implant article is in place, it should remain
in at least partial contact with a biological fluid, such as blood,
internal organ secretions, mucous membranes, cerebrospinal fluid
and the like.
EXAMPLES
Example 1
Synthesis of Poly(L-lactide-co-ethyl-phosphate)
[Poly(LAEG-EOP)]
[0156] 16
P(LAEG-EOP)
[0157] 20g (0.139 mole of
(.sup.3S)-cis-3,6-dimethyl-1,4-dioane-2,5-dione (L-lactide)
(obtained from Aldrich Chemical Company, recrystallized with ethyl
acetate, sublimed, and recrystallized with ethyl acetate again) and
0.432 g (6.94 mmole) of ethylene glycol (99.8%, anhydrous, from
Aldrich) were placed in a 250 mL round-bottomed flask flushed with
dried argon. The flask was closed under vacuum and placed in an
oven heated to 140.degree. C. The flask was kept at this
temperature for about 48 hours with occasional shaking.
[0158] The flask was then filled with dried argon and placed in oil
bath heated to 135.degree. C. Under an argon stream, 1.13 g of
ethyl phosphorodichloridate was added with stirring. After one hour
of stirring, a low vacuum (about 20 mm Hg) was applied to the
system, and it was allowed to stand overnight. One hour before
work-up, a high vacuum was applied. After cooling, the polymer was
dissolved in 200 mL of chloroform and quenched into one liter of
ether twice to an off-white precipitate, which was dried under
vacuum
[0159] It was confirmed by NMR spectroscopy that the polymer
obtained was the desired product,
poly(L-lactide-co-ethyl-phosphate) [P(LAEG-EOP)], as shown in FIGS.
6 and 7.
Example 2
Properties of P(LAEG-EOP)
[0160] A P(LAEG-EOP) polymer where (x or y)/n=10:1 was prepared as
described above in Example 1. The resulting
poly(phosphoester-co-ester) polymer was analyzed by GPC using
polystyrene as a standard, and the resulting graph established an
Mw of 33,000 and an Mn of 4800, as shown in FIG. 7.
[0161] The viscosity was measured in chloroform (CH.sub.3Cl) at
40.degree. C. and determined to be 0.315 dL/g. The polymer was
soluble in ethyl acetate, acetone, acetonitrile, chloroform,
dichloromethane, tetrahydrofuran, N-methylpyrrolidone,
dimethylformamide, and dimethyl sulfoxide. The polymer formed a
brittle film, and the Tg was determined by DSC to be 51.5.degree.
C., as shown in FIGS. 2A and 2B.
Example 3
Synthesis of Poly(L-lactide-co-hexyl-phosphate)
[Poly(LAEC--HOP)]
[0162] A second poly(L-lactide-phosphate) having the following
structure: 17
[0163] was also prepared by the method described in Example 1,
except that hexyl phosphorodichloridate ("HOP") was substituted for
EOP (ethyl phosphorodichloridate).
Example 4
Properties of P(LAEG-EOP) and P(LAEG-Hop)
[0164] The weight-average molecular weight (Mw) of the
phosphoester-co-ester polymer of Example 1, P(LAEG-EOP), and the
polymer of Example 3, P(LAEG-HOP), were first determined by gel
permeation chromatography (GPC) with polystyrene as the calibration
standard, as shown in FIG. 1. Samples of each were then allowed to
remain exposed to room temperature air to test for ambient,
unprotected storage capability. After one month, the Mw was again
determined for each polymer. The results (plotted in FIG. 5) showed
that, while the Mw for p(LAEG-EOP) was reduced by about one-third
after a month of unprotected ambient conditions, the Mw for
p(LAEG-HOP) remained fairly constant, even showing a slight
increase See also FIG. 8.
[0165] Discs for degradation studies were then fabricated from each
polymer by compression molding at 50.degree. C. and a pressure of
200 MPa. The discs were 4 mm in diameter, 1.5 mm in thickness, and
40 mg in weight. The degradation studies were conducted by placing
the discs in 4 mL of 0.1M PBS (pH 7.4) at 37.degree. C. Duplicate
samples were removed at different time points up to eight days,
washed with distilled water, and dried under vacuum overnight.
Samples were analyzed for weight loss and molecular weight change
(GPC), and the results are shown in FIGS. 4A, 4B, 10A and 10B. Both
polymers, P(LAEG-EOP) and P(LAEG-HOP), demonstrated favorable
degradation profiles.
Example 5
In vivo Biocomoatibilitv of P(-LAEG-EOP)
[0166] A 100 mg polymer wafer was formed from P(LAEG-EOP) and, as a
reference, a copolymer of lactic and glycolic acid ["PLGA (RG755)"]
known to be biocompatible. These wafers were inserted between
muscle layers of the right limb of adult SPF Sprague-Dawley rats
under anesthesia. The wafers were retrieved at specific times, and
the surrounding tissues were prepared for histopathological
analysis by a certified pathologist using the following
scoring:
1 Score Level of Irritation 0 No Irritation 0-200 Slight Irritation
200-400 Mild Irritation 400-600 Moderate Irritation More than 600
Severe Irritation
[0167] The results of the histopathological analysis are shown
below in Table 8.
2TABLE 8 Inflammatory Response at Site of Implantation (i.m.) 3 7
14 1 2 3 Polymer Days Days Days Month Mos. Mos. P (LAEG- 130 123
180 198 106 99 EOP) PLGA 148 98 137 105 94 43 (RG755)
[0168] See also FIG. 12. The phosphoester copolymer P(LAEG-EOP) was
shown to have an acceptable biocompatability similar to that
exhibited by the PLGA reference water.
Example 6
Preparation of Microspheres
[0169] Microspheres were made from P(LAEG-EOP) by a solvent
evaporation (double emulsion) method using methylene chloride as a
solvent. The results ate shown in FIG. 3.
Example 7
Preparation of Copolymer Microspheres Containing FITC-BSA with 10%
Theoretical Loading Level
[0170] One hundred M.sub.1 of FITC-BSA solution (100 mg/mL
dissolved in water) was added to a solution of 100 mg of
P(LAEG-EOP) in 1 mL of methylene chloride, and emulsified via
sonicalion for 15 seconds on ice. The resulting emulsion was
immediately poured into 5 mL of vortexing a 1% solution of
polyvinyl alcohol (PVA) in 5% NaCl, and vortexing was maintained
for one minute. The emulsion thus formed was then poured into 20 mL
of a 0.3% PVA solution in 5% NaCl, which was being
stirred-vigorously. Twenty five it of a 2% solution of isopropanol
was added, and the mixture was kept stirring for one hour to ensure
complete extraction. The resulting microspheres were collected via
centrifugation at 3000.times. g, washed 3 times with water, and
freeze dried.
[0171] Different formulations of microspheres were made by using as
the second aqueous phase a 5% NaCl solution or a 5% NaCl solution
also containing 1% PEG 8000. Yet another technique was used in
evaporating the solvent by stirring the mixture overnight, thus
forming microspheres by solvent evaporation.
Example 8
Estimation of Encapsulation Efficiency and Loading Level
[0172] The loading level of FITCESA was determined by assaying for
FITC after hydrolyzing the microspheres with 0.5 N NaOH overnight.
The amount of FITC-BSA was compared with a standard curve that had
been generated by making a series of FITC-BSA solutions in 0.5 N
NTaOH. The encapsulation efficiency of the microspheres was
determined by comparing the quantity of FITC-BSA entrapped with the
initial amount in solution via fluorometry. The encapsulation
efficiency (%) and loading level (%) of EITC-BSA are shown in Table
1 below.
3TABLE 1 Encapsulation Efficiency and Loading Lever of FITC-BSA
Loading (%) High Low Loading Loading (24.98%) (1.5%) Encapsulation
Efficiency (%) 98.10 91.70
Example 9
Cytotoxicity of the Copolymer
[0173] Microspheres containing P(LAEG-EOP) were added to 96well
tissue culture plates at different concentrations Human gastric
carcinoma cells (GT3TKB) were then seeded at a rate of 10.sup.4
cells/well. The cells were then incubated with the microspheres in
the wells for 48 hours at 37.degree. C. The cell proliferation rate
was analyzed by MTT assay, and the results were plotted as %
relative growth vs. concentration of copolymer microspheres in the
tissue culture well, as shown in FIG. 9.
Example 10
Effect of Fabrication Method on the Release of FITC-BSA from
Microspheres
[0174] Fifty mg of microspheres of a polymer of the invention were
suspended in vials containing 10 mL of PBS, and the vials were
shaken in an incubator at 37.degree. C. and at a rate of 220 rpm.
The supernatant fluid was replaced at various time points, and the
amount of FITC-BSA released was analyzed by spectrophotometry at
492 nm. The results were plotted as % cumulative release of
FITC-BSA from the microspheres vs. time in hours, as shown in FIG.
13.
Example 11
Preparation of P(LAEG-EOP) Microspheres Containing Lidocaine Using
Polyvinyl Alcohol as the Non-Solvent Phase
[0175] A solution of 0.5% w/v polyvinyl alcohol (PVA) in deionized
water solution was prepared in a 600 mL beaker by combining 1.05 g
of PVA with 210 mL of deionized water. The solution was stirred for
one hour and filtered. A polymer/drug solution was prepared by
combining 630 mg of polymer and 70 mg of lidocaine in 7 mL or
methylene chloride and mixing by vortex. The PVA solution was mixed
at 500 rpm with an overhead mixer, and the polymer/drug solution
was added dropwise. After 30 minutes of mixing, 200 mL of cold
deionized water was added to the stirring PVA solution. The
resulting mixture was stirred for a total of 3.5 hours. The
microspheres formed were filtered off, washed with deionized water,
and lyophilized overnight.
[0176] Microspheres loaded with 4.2% w/w lidocaine were thus
obtained. Approximately 10 mg of microspheres were placed in a
phosphate buffer saline (0.1M, pH 7.4) at 37.degree. C. on a shaker
and sampled regularly. The results were plotted as s lidocaine
released vs. time in days, as shown in FIG. 16.
Example 12
Prenaration of P(DAEG-EOP)
[0177] The d,l racemic mixture of
poly(L-lactide-co-ethyl-phosphate) ["P(DAEG-EOP)"], was prepared in
the same manner as P(LAEG-EOP), as described in Example 1.
Example 13
Preparation of P(DAEG-EOP) Microspheres With Lidocaine Using
Silicon Oil as the Non-Solvent Phase
[0178] Two percent sorbitan-trioleate, which is commercially
available from Aldrich under the tradename Span-85, in silicon oil
was prepared in a 400 mL beaker by combining 3 ML of Span-85 with
150 mL of silicone oil and mixing with an overhead stirrer set at
500 rpm. A P(DAEG-EOP) polymer/drug solution was prepared by
dissolving 400 mg of the polymer prepared above in Example 9, and
100 mg of lidocaine in 4.5 ML of methylene chloride. The resulting
polymer/drug solution was added dropwise to the silicone oil/span
mixture with stirring. The mixture was stirred for an hour and 15
minutes. The microspheres thus formed were filtered off and washed
with petroleum ether to remove the silicone oil/span mixture, and
lyophilized overnight.
[0179] 450 mg of microspheres loaded with 7.6% w/w lidocaine were
thus obtained. Approximately 10 mg of microspheres were placed in
phosphate buffer saline (0.1M, pH 7.4) at 37.degree. C. on a shaker
and sampled regularly. The results were plotted as % lidocaine
released vs. time in days, as shown in FIG. 17
Example 14
Biocompatibility of Poly(phosphoester) Microspheres in Mouse
Peritoneal Cavity
[0180] The biocompatibility of biodegradable poly(phosphoester)
microspheres of the invention was tested as follows:
[0181] Three 30 mg/mL samples of lyophilized
poly(L-lactide-co-ethyl-phosp- hate) microspheres were prepared,
the first having diameters greater than 75 microns, the second
having diameters within the range of 75-125 microns, and the third
having diameters within the range of 125-250 microns. Each sample
was injected intra-peritoneally into a group of 18 female CD-1 mice
having a starting body weight of 25 g. Animals in each group were
weighed, sacrificed, and necropsied at 2, 7 and 14 days, and at 1,
2 and 3 months. Any lesions detected during the necropsy were
graded on a scale of 0 to 4, with 0 indicating no response to
treatment and 4 indicating a severe response to treatment.
[0182] Inflammatory lesions were observed to be restricted to an
association with the microspheres on peritoneal surfaces or within
fat tissue, and were compatible with foreign body isolation and
encapsulation. Focal to multifocal supportive peritoneal steatitis
with mesothelial hyperplasia was observed at 2-7 days, but
gradually resolved by macrophage infiltration, the formation of
inflammatory giant cells, and fibrous encapsulation of the
microspheres at later sacrifices. Occasional adherence of
microspheres to the liver and diaphragm, with associated
inflammatory reaction, was also seen. Lesions related to
microspheres were not seen within abdominal or thoracic organs.
Microspheres, which were detected throughout the duration of the
study, appeared transparent at early sacrifices but at later times,
developed crystalline material internally. effects on body growth
were observed. The peritoneal reaction was observed to be limited
to areas directly adjacent to the microspheres with no apparent
deleterious effects on major thoracic or abdominal organs.
[0183] The invention being thus described, it will be obvious that
the same may be varied in many ways. Such variations are not to be
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.
* * * * *