U.S. patent application number 09/985874 was filed with the patent office on 2002-04-25 for copolymer and process for preparing the same.
Invention is credited to Asou, Yukiko, Shinoda, Hosei, Tamatani, Hiroaki.
Application Number | 20020048559 09/985874 |
Document ID | / |
Family ID | 18458879 |
Filed Date | 2002-04-25 |
United States Patent
Application |
20020048559 |
Kind Code |
A1 |
Shinoda, Hosei ; et
al. |
April 25, 2002 |
Copolymer and process for preparing the same
Abstract
There are herein disclosed a copolymer having a weight-average
molecular weight of 1,000 to 100,000 which comprises, as repeating
structure units, both of a succinimide unit represented by the
structural formula (1) 1 and a hydroxycarboxylic acid unit
represented by the structural formula (2) 2 wherein R is a methyl
group or a hydrogen atom, and a process for preparing a copolymer
which comprises a polymerization step of heating a mixture of
aspartic acid and a cyclic ester compound.
Inventors: |
Shinoda, Hosei; (Kanagawa,
JP) ; Asou, Yukiko; (Kanagawa, JP) ; Tamatani,
Hiroaki; (Kanagawa, JP) |
Correspondence
Address: |
Robert G. Mukai
BURNS, DOANE, SWECKER & MATHIS, L.L.P.
P.O. Box 1404
Alexandria
VA
22313-1404
US
|
Family ID: |
18458879 |
Appl. No.: |
09/985874 |
Filed: |
November 6, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09985874 |
Nov 6, 2001 |
|
|
|
09219452 |
Dec 23, 1998 |
|
|
|
Current U.S.
Class: |
424/78.36 ;
528/289 |
Current CPC
Class: |
C08G 73/16 20130101;
C08G 73/1092 20130101; A61K 9/1641 20130101 |
Class at
Publication: |
424/78.36 ;
528/289 |
International
Class: |
A61K 031/785; C08G
073/16 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 25, 1997 |
JP |
358356/1997 |
Claims
What is claimed is:
1. A copolymer having a weight-average molecular weight of 1,000 to
100,000 which comprises, as repeating structure units, both of a
succinimide unit represented by the structural formula (1) 18and a
hydroxycarboxylic acid unit represented by the structural formula
(2) 19wherein R is a methyl group or a hydrogen atom.
2. The copolymer according to claim 1 wherein the ratio of the
succinimide unit represented by the structural formula (1) is in
the range of 1 to 33 mol %, and the ratio of the hydroxycarboxylic
acid unit represented by the structural formula (2) is in the range
of 67 to 99 mol %.
3. The copolymer according to claim 1 which comprises both of a
polysuccinimide segment represented by the structural formula (3)
20wherein m is an integer of 1 to 100, and a polyhydroxycarboxylic
acid segment represented by the structural formula (4) 21wherein R
is a methyl group or a hydrogen atom; and n is an integer of 1 to
1,000, and in which the ratio of the succinimide unit is in the
range of 1 to 33 mol %, and the ratio of the hydroxycarboxylic acid
unit is in the range of 67 to 99 mol %.
4. The copolymer according to claim 1 which is a branched copolymer
having all of a segment A represented by the structural formula (5)
22wherein x is an integer of 1 to 100, a segment B represented by
the structural formula (6) 23wherein y is 0 or a positive integer
of 100 or less; and M is a metal or a hydrogen atom, and a segment
C represented by the structural formula (7) 24wherein z is an
integer of 4 to 1,000; and R is a methyl group or a hydrogen atom,
and in which the ratio of a unit containing a structure represented
by the following structural formula (8) derived from aspartic acid
is in the range of 1 to 33 mol %, 25and the ratio of the
hydroxycarboxylic acid unit is in the range of 67 to 99 mol %, and
a molecular terminal comprises at least one group selected from the
group consisting of an amino group, a hydroxy group, a carboxyl
group and a carboxylate group.
5. The copolymer according to claim 1 which contains a repeating
structure unit represented by the structural formula (9) 26wherein
p and q is each 0 or a positive integer of 1,000 or less; and R is
a methyl group or a hydrogen atom, and/or a repeating structure
unit represented by the structural formula (10) 27wherein r and s
is each 0 or a positive integer of 1,000 or less; and R is a methyl
group or a hydrogen atom, and in which the ratio of a unit
containing a structure represented by the following structural
formula (11) derived from aspartic acid in the copolymer is in the
range of 1 to 33 mol %, 28and the ratio of the hydroxycarboxylic
acid unit is in the range of 67 to 99 mol %.
6. The copolymer according to claim 1 which is represented by the
following structural formula (12) 29wherein p, r and s are each 0
or a positive integer, provided that three of p, r and s are not
simultaneously 0; q is an integer of 1 or more, and (p+r+s)/(q+1)
is in the range of 2 to 100; and R is a hydrogen atom or a methyl
group.
7. A copolymer represented by the following structural formula
(13), which is obtained from the copolymer of claim 1, 30wherein p,
r and s are each 0 or a positive integer, provided that three of p,
r and s are not simultaneously 0; q is an integer of 0 or a
positive integer, (p+r+s)/(q+1) is in the range of 2 to 100; and R
is a hydrogen atom or a methyl group; and M is a metal or a
hydrogen atom.
8. The copolymer according to claim 1 which has a Tg of 40.degree.
C. or more, and is molten at 100.degree. C. or less.
9. A process for preparing a copolymer which comprises a
polymerization step of heating a mixture of aspartic acid and a
cyclic ester compound to obtain the copolymer having both of a
succinimide unit and a hydroxycarboxylic acid unit as repeating
structural units.
10. The process for preparing the copolymer according to claim 9
which further contains a hydrolysis step of hydrolyzing the
succinimide unit of the copolymer obtained in the polymerization
step to open at least a part of the rings of the copolymer, thereby
obtaining the copolymer having both of at least the aspartic acid
unit and the hydroxycarboxylic acid unit.
11. The process for preparing the copolymer according to claim 9
wherein a mixed molar ratio of aspartic acid to the cyclic ester
compound is in the range of 1/1 to 1/50.
12. The process for preparing the copolymer according to claim 9
wherein the cyclic ester compound is lactide and/or glycolide.
13. The process for preparing the copolymer according to claim 9
wherein a mixture of aspartic acid, and lactide and/or glycolide is
heated at 120 to 230.degree. C. in the polymerization step.
14. The process for preparing the copolymer according to claim 10
wherein the hydrolysis is carried out at a pH of 6 to 11 in the
hydrolysis step.
15. A sustained releasing drug which comprises the copolymer of
claim 1 or 7 and an effective component.
16. The sustained releasing drug according to claim 15 having a
capsule form which comprises the copolymer of claim 1 or 7 as an
outer phase and an effective component as an inner phase.
17. The sustained releasing drug according to claim 15 having a
sphere form which comprises a mixture of the copolymer of claim 1
or 7 and an effective component.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to a copolymer which is a
novel compound useful as a base material for a sustained releasing
drug and which has both of a succinimide unit and/or an aspartic
acid unit as well as a lactic acid unit and/or a glycolic acid
unit, and a process for preparing the above copolymer.
[0003] 2. Description of the Related Art
[0004] Heretofore, there has been the approach of applying a
biologically absorbable polymer to a DDS (a drug delivery system).
The DDS means a system in which a drug including the biologically
absorbable polymer as a base material can be sustaining-released by
a proper technique.
[0005] Here, typical examples of the above proper technique include
a method of blending the biologically absorbable polymer with the
drug, a method of microcapsulating the drug with the biologically
absorbable polymer, and a method of immobilizing the drug on the
biologically absorbable polymer.
[0006] Typical examples of the above biologically absorbable
polymer include poly-.alpha.-hydroxy acids such as a polylactic
acid (PLA) and a polyglycolic acid (PGA).
[0007] For example, Japanese Patent Application Laid-Open No.
64824/1987 discloses a method which comprises subjecting, to a ring
opening polymerization, glycolide (GLD) which is a cyclic dimer of
glycolic acid and lactide (LTD) which is a cyclic dimer of lactic
acid, thereby obtaining a low-molecular weight polydisperse lactic
acid-glycolic acid copolymer (PLGA) useful as the base material for
a sustained releasing drug.
[0008] On the other hand, in the DDS just described, the sustained
releasing behavior of the drug in which the biologically absorbable
polymer is used as the base material of the sustained releasing
drug is known to variously change on the basis of a specific
interaction between the drug and the biologically absorbable
polymer. In recent years, therefore, it has been desired to make
the drugs having various structures sustained releasable, but only
by selecting the biologically absorbable polymer as the base
material from already existent polymers such as PLGA, it is often
difficult to design the DDS which can express a desired sustained
release speed, sustained release period, sustained release pH and
the like.
[0009] In view of such a technical background, a novel biologically
absorbable polymer material has been desired as the base material
for the sustained releasing drug.
[0010] Furthermore, when the sustained releasing drug having a form
of microspheres, microcapsules or the like is manufactured by an
emulsion method which has heretofore been used, an organic solvent
is used and hence a solvent removal step is required, so that it is
necessary to validate that the remaining solvent in the drug is at
such a level as to be substantially acceptable.
[0011] Accordingly, there is also a demand that a drug formulation
can be achieved without using any solvent by thermally melting the
polymer and then mixing it with the drug. However, for example, an
optically active PLA has a melting point of 160 to 180.degree. C.,
and if it is molten at this temperature, there exists a problem
that the drug thermally decomposes. If the molecular weight of the
PLA is reduced, the melting point also lowers, but according to the
knowledge of the present inventors, the PLA has a high melting
point of 120.degree. C. or more even at a molecular weight of about
2000 to 3000. On the other hand, if the molecular weight of the PLA
is less than the above level, the PLA becomes a syrup state, which
makes it difficult to prepare the microspheres or the like.
Therefore, it has been desired that the biologically absorbable
polymer which can be used particularly as the base material for the
sustained releasing drug among medical materials has a low melting
point.
[0012] Ganpat L. Jain et al. disclose a certain kind of random
copolymer of lactic acid and aspartic acid [Ganpat L. Jain et al.,
Makromol. Chem., Vol. 182, p. 2557-2561 (1981)]. Herein, Jain et
al. describe a technique in which aspartic acid and lactic acid are
subjected to dehydration-polycondensation at an aspartic
acid/lactic acid ratio of 2:1 to 0.5:1 at 150.degree. C. under
reduced pressure for 5 hours to obtain a lactic acid-aspartic acid
copolymer of aspartic acid:lactic acid=9:1 to 1.77:1.
[0013] However, when lactic acid is copolymerized with aspartic
acid by this technique, a low-molecular weight random copolymer
having a wide molecular weight distribution is merely obtained, and
its yield is also low. In addition, this polymer has a high melting
point, and it is poor in melting workability and moldability and
its use purpose as a medical material is restricted.
SUMMARY OF THE INVENTION
[0014] An object of the present invention is to provide a novel
copolymer and process for preparing the same, which is suitable as,
for example, a base material for a sustained releasing drug, can
typically be softened or molten in such a low temperature range
that a drug for use in a DDS does not thermally decompose, is an
unsticky solid at ordinary temperature (e.g., 25.degree. C., or
less than 40.degree. C.), and is soluble in various kinds of
solvents.
[0015] The present inventors have intensively investigated with the
intention of achieving the above objects, and as a result, it has
been found that when aspartic acid is heated together with lactide,
glycolide or the like to perform polymerization, a novel
biologically absorbable copolymer having both of a
hydroxycarboxylic acid unit and a succinimide unit in its structure
can be obtained, and this copolymer is solid at ordinary
temperature, is molten at 100.degree. C. or less, is soluble in
various kinds of solvents, and shows a particular hydrolysis
behavior. In consequence, the present invention has been
completed.
[0016] That is to say, the present invention is directed to a
copolymer having a weight-average molecular weight of 1,000 to
100,000 which comprises, as repeating structure units, both of a
succinimide unit represented by the structural formula (1) 3
[0017] and a hydroxycarboxylic acid unit represented by the
structural formula (2) 4
[0018] wherein R is a methyl group or a hydrogen atom.
[0019] Furthermore, the present invention is directed to a process
for preparing a copolymer which comprises a polymerization step of
heating a mixture of aspartic acid and a cyclic ester compound to
obtain the copolymer having both of a succinimide unit and a
hydroxycarboxylic acid unit as repeating structural units.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0020] The structure of a copolymer according to the present
invention which has at least both of a succinimide unit and a
hydroxycarboxylic acid unit as repeating structure units can be
confirmed by a known analytical means such as a nuclear magnetic
resonance (NMR) spectrum measurement or an infrared absorption (IRY
spectrum measurement.
[0021] For example, according to the IR spectrum measurement, there
can be observed characteristic absorptions of a carbonyl bond of
the succinimide unit as well as another carbonyl bond of a lactic
acid unit and/or a glycolic acid unit.
[0022] Furthermore, for example, according to the NMR spectrum
measurement, there can be clearly confirmed peaks derived from a
methylene proton and a methine proton of the succinimide unit as
well as peaks derived from a methyl proton and a methine proton of
the lactic acid unit and/or a methylene proton of the glycolic acid
unit. When an NMR measuring device having a high resolving power is
used, there can be slightly observed fine peaks such as peaks
derived from a proton of an amide group and a methyl proton
adjacent to the amide group as well as peaks derived from branches
and chain sequences (inclusive of groups adjacent to the
succinimide unit, the aspartic acid unit, the lactic acid unit
and/or the glycolic acid unit).
[0023] A typical example of the copolymer according to the present
invention is a copolymer having a highly dimensional structure
which is called a block polymer, a graft polymer, a graft block
polymer or a hyper branched polymer in this polymeric chemical
field. More concretely, the example of the copolymer is a copolymer
having a structure in which a polysuccinimide segment mainly having
the succinimide unit as the repeating structure unit is linked with
a polyhydroxycarboxylic acid segment having the hydroxycarboxylic
acid unit as the repeating structure unit in a block state and/or a
branched state.
[0024] The block polymer, graft polymer, graft block polymer or
hyper branched polymer of the present invention preferably
comprises both of a polysuccinimide segment represented by the
structural formula (3) 5
[0025] wherein m is an integer of 1 to 100, and a
polyhydroxycarboxylic acid segment represented by the structural
formula (4) 6
[0026] wherein R is a methyl group or a hydrogen atom; and n is an
integer of 1 to 1,000, and in which the ratio of the succinimide
unit is in the range of 1 to 33 mol %, and the ratio of the
hydroxycarboxtylic acid unit is in the range of 67 to 99 mol %.
[0027] Furthermore, one example of the copolymer of the present
invention is a polymer having a structure represented by the
following structural formula (12): 7
[0028] wherein p, r and s are each 0 or a positive integer,
provided that three of p, r and s are not simultaneously 0; q is an
integer of 1 or more, and (p+r+s)/(q+l) is in the range of 2 to
100; and R is a hydrogen atom or a methyl group.
[0029] In this case, fundamentally, each of a polysuccinimide chain
and a polyhydroxycarboxylic acid chain has a blocking tendency, and
these chains are each present as a segment in the molecule of the
copolymer.
[0030] Furthermore, in the copolymer of the present invention, at
least a part of the succinimide unit can be in the ring opening
state. In this case, the copolymer is preferably a branched
copolymer having all of a segment A represented by the structural
formula (5) 8
[0031] wherein x is an integer of 1 to 100, a segment B represented
by the structural formula (6) 9
[0032] wherein y is 0 or a positive integer of 100 or less; and M
is a metal or a hydrogen atom, and a segment C represented by the
structural formula (7) 10
[0033] wherein z is an integer of 4 to 1,000; and R is a methyl
group or a hydrogen atom.
[0034] Furthermore, the copolymer of the present invention can
include aspartic acid units represented by the following structural
formulae (9) and (10) jumbled in the polysuccinimide segment.
11
[0035] wherein p, q, r and s are each 0 or a positive integer of
1000 or less; and R is a methyl group or a hydrogen atom.
[0036] Moreover, the carboxyl group at the terminal of the
molecular chain is not always a COOH group. For example, it may
form a salt with a base such as an alkali metal, an alkaline earth
metal or an amine.
[0037] In view of physical properties and the like, the molecular
weight of the copolymer according to the present invention is in
the range of 1,000 to 100,000 in terms of its weight-average
molecular weight.
[0038] With regard to the composition of the copolymer according to
the present invention, it is preferred that the ratio of the
succinimide unit is in the range of 1 to 33 mol %, and the ratio of
the hydroxycarboxylic acid unit is in the range of 67 to 99 mol %.
In the case that at least a part of the succinimide unit is in the
ring opening state, it is preferred that the ratio of the unit
including the structure represented by the following structural
formula (11) which is derived from aspartic acid is in the range of
1 to 33 mol %: 12
[0039] and the ratio of the hydroxycarboxylic acid unit is in the
range of 67 to 99 mol %. The unit including the structure
represented by the above structural formula (11) which is derived
from aspartic acid is a general term for the succinimide unit and a
polyaspartic acid unit obtained by the ring opening of this
succinimide unit.
[0040] Next, a process for preparing the copolymer of the present
invention will be described.
[0041] One process for preparing the copolymer of the present
invention is characterized by heating a mixture of aspartic acid
and a cyclic ester compound.
[0042] Aspartic acid which can be used herein may be an optically
active L-form, D-form or DL-form. In order to obtain the copolymer
having a high-molecular weight, it is preferable to use high-purity
aspartic acid in which the content of impurities such as fumaric
acid and maleic acid is 1% by weight or less.
[0043] The cyclic ester compound which can be used herein is a
compound in which a hydroxycarboxylic acid is dehydrated and
cyclized, and preferable examples of the cyclic ester compound
include lactide, glycolide, caprolactone, propiolactone,
butyrolactone and valerolactone, and lactide and glycolide are
particularly preferable. As lactide, any of L-lactide, D-lactide,
DL-lactide and racemic lactide can be used.
[0044] The cyclic ester compound to be used may contain a hydroxy
acid and water, but the amount of them is preferably 30 mol % or
less based on the cyclic ester compound. During reaction,
predetermined amounts of the hydroxy acid, water and an alcohol may
be added to the cyclic ester compound for the purpose of adjusting
a reaction rate and the molecular weight of the produced copolymer.
Similarly, the amounts of them are preferably 30 mol % or less
based on the cyclic ester compound.
[0045] If the feed composition ratio of the cyclic ester compound
to aspartic acid is too high, aspartic acid is scarcely
incorporated into the polymer, so that polyhydroxycarboxylic acids
alone such as PLA, PGA, PLGA and polycaprolactone are liable to be
produced and hence it is difficult to obtain the copolymer which is
the target product of the present invention. On the other hand, if
the feed composition ratio of aspartic acid is too high, the block
chain of the lactic acid unit and/or the glycolic acid unit
scarcely extends unpreferably. In view of the above points, the
feed composition ratio of aspartic acid to the cyclic ester
compound is preferably in the range of about 1:1 to 1:50.
[0046] According to the preparation process of the present
invention, the polymer can be sufficiently obtained, even if any
solvent is not used during the reaction. However, for the purposes
of shortening a reaction time and increasing the molecular weight
of the produced polymer, a certain kind of catalyst may be used.
Examples of the preferable catalyst include metals such as tin,
zinc and titanium, metallic salt compounds such as tin octanoate
and tin tetrechloride, organic acids and inorganic acids.
[0047] The control of a reaction temperature is important. During
the whole reaction steps, the reaction is carried out preferably in
the range of 120.degree. C. to 230.degree. C. However, in an early
stage of the reaction, the reaction is preferably carried out at a
high temperature of at least 140.degree. C. in order to accelerate
the dehydration of aspartic acid. This temperature is preferably in
the range of 160.degree. C. to 230.degree. C., more preferably
180.degree. C. to 220.degree. C. In the latter half of the
reaction, the temperature is preferably lower than in the early
stage of the reaction in order to inhibit the decomposition of the
produced polymer. This temperature is preferably in the range of
120.degree. C. to 200.degree. C.
[0048] A polymerization reaction mechanism in the preparation
process of the present invention is different from a polymerization
mechanism of a conventional method in which aspartic acid, lactic
acid and/or glycolic acid are heated and dehydrated (hereinafter
referred to as "the direct dehydrocondensation method"). This can
easily be understood from a fact that a reaction proceeding state,
the molecular weight of the produced polymer, a molecular weight
distribution and a yield in the process of the present invention
are different from those in the conventional method.
[0049] Next, a suitable embodiment of the present invention will be
described in accordance with an example in which the cyclic ester
compound is lactide and/or glycolide.
[0050] In the early stage of the reaction, glycolide and/or lactide
having a melting point in the vicinity of 80 to 90.degree. C. is
first molten and stirred, while an unmolten aspartic acid powder
floats. Afterward, aspartic acid begins to polymerize by heating,
while dehydrated. By the utilization of water generated by the
dehydration of aspartic acid, the ring of lactide and/or glycolide
is opened, and while a hydroxy acid produced by the ring opening
opens the rings of other lactide and/or glycolide, the
polymerization proceeds. Afterward, copolymerization occurs between
aspartic acid or the polymer of aspartic acid and lactide and/or
the polymer of glycolide, whereby aspartic acid or the polymer of
aspartic acid which has been in a granular state is solubilized and
becomes transparent, and a reaction solution becomes uniformed.
Gradually, the viscosity of the reaction solution increases.
[0051] On the other hand, when the direct dehydrocondensation
method, wherein aspartic acid is reacted with lactic acid and/or
glycolic acid, is conducted, aspartic acid is quickly solved in
lactic acid and/or glycolic acid in the early stage of the reaction
by heating, and a transparent and uniform solution is formed. As
the result, aspartic acid is copolymerized with lactic acid and/or
glycolic acid without polymerization of aspartic acid each other to
form a copolymer having high randomness.
[0052] According to the preparation process of the present
invention, after most of aspartic acid or the polymer of aspartic
acid is consumed and the reaction solution becomes uniformed, i.e.,
in the latter half of the reaction, the pressure of the reaction
system is preferably reduced to accelerate the dehydration. For the
acceleration of the dehydration, a solvent which can make water
azeotropic may be added, and reflux may be then carried out to
remove water from the resultant effluent.
[0053] A reaction time can be suitably decided in consideration of
the reaction temperature, the presence/absence of the catalyst and
the molecular weight of the polymer, but it is in the range of
about 2 to 100 hours.
[0054] After completion of the reaction, the purifying isolation of
the produced polymer from the reaction mixture can be performed by
a known purifying isolation technique such as a reprecipitation
method or a separating precipitation method. For example, the
reaction mixture is dissolved in dimethylformamide (DMF), and the
solution is then poured into water. Afterward, the insoluble
polymer precipitate is collected by filtration or centrifugal
separation. The preparation process of the present invention
permits the production of the polymer having a higher molecular
weight and a narrower molecular weight distribution, as compared
with the direct dehydrocondensation method. In addition, the
collection ratio of the polymer by a purification such as the
reprecipitation is high.
[0055] One aspect of the copolymer of the present invention is the
polymer obtained by heating the mixture of aspartic acid and
lactide and/or glycolide, and this copolymer is different in the
structure from a copolymer obtained by the conventional direct
dehydrocondensation method. This difference of the structure can be
confirmed by a known analytical means. That is to say, for example,
in NMR spectra, peaks having low intensities are different, whereby
it can be confirmed that the extent of branching and the blocking
tendency are definitely different.
[0056] Furthermore, the difference of the structure between both
the methods leads to a difference of the hydrolysis behavior. For
example, reference will be made to the same copolymers in which the
composition ratio of the unit derived from aspartic acid to the
unit derived from the hydroxy acid is 1:5. In the case of the
copolymer of the present invention, the whole polymer becomes
water-soluble relatively rapidly (in a time of several hours to
several tens hours) in water at a temperature in the vicinity of a
body temperature and at the same pH as in the human body, and it
once disappears, but it becomes water insoluble again in a period
of several days to several tens days to produce a precipitate. On
the other hand, in the case of the copolymer obtained by the direct
dehydrocondensation method, the copolymer partially becomes
water-soluble, but the water-insoluble polymer is continuously held
over several tens days.
[0057] In addition, the difference of the structure between both
the methods also appears as a difference of solubility. Moreover,
with regard to the molecular weight distribution, a difference can
also be observed.
[0058] The difference of the structure is, needless to say, based
on the difference between the preparation methods. The structure of
the copolymer according to the present invention is derived from
its specific preparation process.
[0059] Furthermore, the present invention covers a copolymer
including at least the aspartic acid unit and the lactic acid unit
and/or the glycolic acid unit as the repeating structure units
which can be obtained by first heating a mixture of aspartic acid
and lactide and/or glycolide and then hydrolyzing the succinimide
unit of the resultant polymer to open a ring (this copolymer will
be hereinafter referred to as "the hydrolysis type copolymer"). One
example of this hydrolysis type copolymer is a polymer having the
structure represented by the structural formula (13): 13
[0060] wherein p, r and s are each 0 or a positive integer,
provided that three of p, r and s are not simultaneously 0; q is 0
or a positive integer, and (p+r+s)/(q+l)=2 to 100; R is a hydrogen
atom or a methyl group; and M is a metal or a hydrogen atom.
[0061] A difference between the structural formulae (14) and (15)
is the presence/absence of an opened imide ring. A composition
ratio between the opened ring structure and the unopened ring
structure can be changed by adjusting the extent of the hydrolysis,
and the copolymer having any composition ratio is within the scope
of the present invention.
[0062] The aspartic acid unit contained in the structure of the
copolymer according to the present invention is a unit in which an
.alpha.-amide type monomer unit and a .beta.-amide type monomer
unit can simultaneously exist, and a ratio between both the amide
type monomer units is not particularly limited.
[0063] The hydrolysis type copolymer can be prepared by suspending
or dissolving the copolymer having the succinimide unit obtained by
the above preparation process in water or a mixed solvent of a
water-readily soluble solvent and water, and then simply heating
the suspension or the solution, or adding an aqueous alkali
solution thereto. The water-readily soluble solvent means a solvent
which can dissolve at least 5% by weight of water therein, and
examples of the water-readily soluble solvent include alcohols such
as methanol and ethanol, acetone and acetonitrile. In the case that
the alkali is added, the molecular weight of the copolymer lowers
if the alkali is excessively added. Hence, this point should be
noted.
[0064] As the aqueous alkali solution for use in the hydrolysis, a
known aqueous solution can be used. Example of the aqueous alkali
solution include an aqueous sodium hydroxide solution, an aqueous
potassium hydroxide solution, an aqueous ammonia solution and an
aqueous sodium carbonate solution.
[0065] The hydrolysis scarcely proceeds under acidic conditions. On
the other hand, strong alkali conditions are also inconvenient,
because the cleavage of the polymer chain easily occurs. In
consideration of these points, it is preferred that the hydrolysis
is carried out in the pH range of 6 to 11.
[0066] In the case that a usually known PLA or PLGA is an oligomer
having a low molecular weight of several thousand or so, it is in a
syrup state or a sticky solid, whereas the copolymer of the present
invention is a less sticky solid at room temperature (ordinary
temperature) though it has a low molecular weight, so that it can
be easily handled. The glass transition point (Tg) of the copolymer
is in the range of 40.degree. C. or more (about 40 to 60.degree.
C.), and it is easily molten at a relatively low temperature (e.g.,
100.degree. C. or less). In addition, its melting viscosity is
lower than the already existing PLA, PLGA or the like, and so it
can be conveniently molten and mixed with an sustained releasing
drug.
[0067] The copolymer of the present invention can be readily
dissolved in various kinds of organic solvents and can be easily
molten and molded at a relatively low temperature, and hence it can
be molded into microspheres, microcapsules or the like. Therefore,
the copolymer is useful as a resin for the base material of a
sustained releasing drug.
[0068] That is to say, the employment of the copolymer according to
the present invention enables the preparation of the sustained
releasing drug comprising this copolymer and a drug. This sustained
releasing drug may take the capsule form in which an outer phase is
constituted of the copolymer, and an inner phase is constituted of
the drug. Alternatively, the sustained releasing drug may take the
sphere form comprising a mixture of the copolymer of the present
invention and the drug.
[0069] The content of the present invention will be described in
detail in accordance with examples. Incidentally, the values of
physical properties shown in the examples were measured as
follows.
[0070] (1) Weight-average Molecular Weight (Mw) and Molecular
Weight Distribution (Mw/Mn) of a Polymer
[0071] A sample was dissolved in dimethylformamide
(concentration=0.5% by weight), and the weight-average molecular
weight (Mw) and the molecular weight distribution (Mw/Mn) of the
polymer were measured by gel permeation chromatography (GPC). As a
control substance, polystyrene was used.
[0072] (2) Infrared Absorption (IR) Spectrum
[0073] A polymer sample powder was well mixed with a KBr powder,
and the mixture was then pressed while deaerated to form tables,
and a spectrum was then measured by an FTAIR device (Fourier
analysis type, integrating type infrared spectrometer).
[0074] (3) Nuclear Magnetic Resonance (NMR) Spectrum
[0075] A sample was dissolved in deuterized dimethyl sulfoxide
(concentration=7% by weight), and H-NMR spectrum (400 MHz) and
C-NMR spectrum (100 MHz) were measured at room temperature by the
use of a nuclear magnetic resonance measuring device.
[0076] (4) Measurement by a Differential Scanning Calorimeter
(DSC)
[0077] Measurement was done at -50.degree. C. to 250.degree. C.
under a temperature rise velocity of 10.degree. C./min by a
differential scanning calorimeter.
[0078] (5) Solubility Test of a Polymer
[0079] 200 mg of a polymer sample were added to 2 ml of a solvent,
heated up to 40 to 50.degree. C. with stirring, and then cooled to
room temperature again, and a solubility of the polymer was
inspected. Evaluation was made in accordance with 4 grades of
"completely dissolved", "half dissolved", "swelled" and
"undissolved".
EXAMPLE 1
[0080] 13.3 g (0.1 mol) of L-aspartic acid and 28.8 g (0.2 mol) of
L-lactide were placed in a glass reactor equipped with a stirring
device and a vent. In this case, a molar ratio of fed aspartic acid
to lactic acid became 1:4. The reactor was immersed in an oil bath
at 180.degree. C., followed by stirring. Lactide having a melting
point of 98.degree. C. was molten, and heating was continued in a
condition that a white powder of insoluble aspartic acid was
floating. The powder gradually disappeared in a period of about 30
minutes to 1 hour, and the viscosity of the yellow reaction
solution rose. After 1.5 hours from the start of the heating, the
pressure in the reaction system was slowly reduced, so that 1 mmHg
was reached after 2 hours. The heating was further continued for 2
hours, and the reactor was taken out of the oil bath and the
reaction solution was collected and then cooled for solidification.
The resultant lightly yellowish brown semitransparent solid was
ground to obtain a powdery polymer. An Mw and an Mw/Mn of the
obtained polymer was 6500 and 7.4, respectively.
[0081] After 10 g of this polymer were dissolved in 20 g of DMF,
the solution was poured into 400 ml of water, and the resultant
precipitate was then collected to thereby purify the polymer. A
purification yield was 81%. An Mw and an Mw/Mn of the purified
polymer was 9400 and 1.22, respectively.
[0082] For the thus purified polymer, IR measurement was carried
out, and as a result, a broad absorption was present at 3420
cm.sup.-1, and other characteristic absorption peaks were observed
at 3000 cm.sup.-1, 2950 cm.sup.-1, 1723 cm.sup.-1, 1720 cm.sup.-1,
1460 cm.sup.-1, 1390 cm.sup.-1, 1360 cm.sup.-1, 1210 cm.sup.-1,
1190 cm.sup.-1, 1140 cm.sup.-1, 1100 cm.sup.-1 and 1050
cm.sup.-1.
[0083] The H-NMR of the purified polymer was measured, and in
consequence, there were observed a peak derived from a methyl
proton of a lactic acid unit at 1.3 to 1.6 ppm, a peak derived from
a methylene proton of a succinimide unit at 2.5 to 3.3 ppm, a peak
derived from a methine proton of the lactic acid unit in the
vicinity of 5.0 ppm, and a peak derived from a methine proton of
the succinimide unit in the vicinity of 5.2 ppm. In addition, peaks
derived from amide protons having the following structural formulae
(14) and (15) were confirmed at 8.1 to 8.8 ppm. 14 15
[0084] Furthermore, peaks derived from methyl protons having the
above structural formulae (14) and (15) were confirmed at 4.6 to
4.7 ppm.
[0085] Additionally, in the H-NMR spectrum, there were present
peaks derived from, for example, polymer terminals and branched
portions at 1.0 ppm, 3.7 ppm, 4.0 ppm, 4.2 ppm, 5.4 ppm, 5.6 ppm
and 7.2 ppm, though the intensity of these peaks was low.
[0086] According to the results of the NMR measurement, a
composition ratio of a unit derived from aspartic acid (an aspartic
acid unit and a succinimide unit) to the lactic acid unit in the
polymer was 1:3.9.
[0087] On the basis of the analysis of the NMR spectrum and the IR
spectrum, the structure of the obtained polymer could be presumed
to be substantially as shown by the following structural formula
(16). 16
[0088] wherein p, q, r and s are each 0 or a positive integer.
[0089] However, it could be presumed that a part of the succinimide
unit in the structural formula (16) was opened, and structural
moieties of the following structural formulae (17) and (18) were
contained therein. 17
[0090] wherein m and n are each 0 or a positive integer.
[0091] furthermore, the obtained polymer was an unsticky solid at
ordinary temperature, and according to DSC measurement, the glass
transition point was shown at 41.degree. C. No absorption of heat
by melting a crystal was shown so that the polymer was
noncrystalline.
[0092] The solubilities of the polymer in various solvents were as
follows:
[0093] Completely dissolved: Dimethyl formamide, dimethyl
sulfoxide, acetone, tetrahydrofuran, acetonitrile and ethyl
acetate.
[0094] Half dissolved (a part of insolubles remained):
Chloroform.
[0095] Swelled (or gummed): Methanol, ethanol and 2-propanol.
[0096] Undissolved: Water and toluene.
[0097] The obtained polymer powder was placed in a test tube and a
sufficient amount of a phosphoric acid buffer solution having a pH
of 7.3 was added thereto, and it was kept in a thermostatic chamber
at 37.degree. C. The polymer powder disappeared in a period of
several hours to 20 hours, and the solution in the test tube became
slightly yellow semitransparent. This reason is that an imide ring
in the polymer structure was hydrolyzed to produce a carboxyl
group, so that the polymer became water-soluble.
REFERENCE EXAMPLE 1
[0098] L-lactide alone was heated at 180.degree. C. in the same
manner as in Example 1, so that a slightly yellow semitransparent
solution could be formed, but viscosity did not rise. The solution
was cooled and hence solidified, and the resultant solid was
collected and then inspected. As a result, it was apparent that the
solid was L-lactide containing a small amount, i.e., several
percent by weight of a lactic acid oligomer (dimer to decamer or
so).
REFERENCE EXAMPLE 2
[0099] Aspartic acid alone was heated at 180.degree. C. in the same
manner as in Example 1, and it scarcely changed in about 4 hours.
An aspartic acid powder was collected.
[0100] Next, aspartic acid was heated at 220.degree. C. for 2
hours, so that a brown powder was obtained. By NMR and IR
measurement, it was confirmed that this brown powder was a
polysuccinimide. Its Mw was 15,000.
[0101] In DSC measurement, this polysuccinimide did not show a
definite melting heat absorption peak, and it only thermally
decomposed at 250.degree. C. or more.
[0102] The solubilities of the obtained polysuccinimide in various
solvents were as follows:
[0103] Half dissolved (a part of insolubles remained):
Dimethylformamide. Undissolved: Chloroform, tetrahydrofuran,
acetone, acetonitrile, ethanol, methanol, water and toluene.
EXAMPLE 2
[0104] 13.3 g (0.1 mol) of L-aspartic acid and 36.0 g (0.25 mol) of
L-lactide were placed in a glass reactor equipped with a stirring
device and a vent. In this case, a molar ratio of fed aspartic acid
to lactic acid became 1:5. The reactor was immersed in an oil bath
at 180.degree. C., followed by stirring. Lactide having a melting
point of 98.degree. C. was molten, and heating was continued in a
condition that a white powder of insoluble aspartic acid was
floating. The powder gradually disappeared in a period of about 30
minutes to 1 hour, and the viscosity of the yellow reaction
solution rose. After 1.5 hours from the start of the heating, the
pressure in the reaction system was slowly reduced, so that 1 mmHg
was reached after 2 hours. After the heating was further continued
for 2 hours, the temperature of the oil bath was lowered to
160.degree. C., and the reaction was further continued for 15
hours. The reactor was taken out of the oil bath, and the reaction
solution was collected and then cooled for solidification. The
resultant lightly yellowish brown semitransparent solid was ground
to obtain a powdery polymer. An Mw and an Mw/Mn of the polymer was
14,700 and 1.38, respectively.
[0105] After 10 g of this polymer were dissolved in 20 g of DMF,
the solution was poured into 400 ml of water, and the resultant
precipitate was then collected to thereby purify the polymer. A
purification yield was 94%. An Mw and an Mw/Mn of the purified
polymer was 16,300 and 1.37, respectively.
[0106] According to the results of the NMR measurement, a
composition ratio of a unit derived from aspartic acid (an aspartic
acid unit and a succinimide unit) to the lactic acid unit in the
polymer was 1:5.1.
[0107] According to DSC measurement, the glass transition point was
shown at 52.degree. C. No absorption of heat by melting a crystal
was shown so that the polymer was noncrystalline.
[0108] The solubilities of the polymer in various solvents were as
follows:
[0109] Completely dissolved: Dimethyl formamide, dimethyl
sulfoxide, acetone, tetrahydrofuran, acetonitrile and ethyl
acetate.
[0110] Half dissolved (a part of insolubles remained):
Chloroform.
[0111] Swelled (or gummed): Methanol and ethanol.
[0112] Undissolved: Water and toluene.
[0113] The obtained polymer powder was placed in a test tube, and a
sufficient amount of a phosphoric acid buffer solution having a pH
of 7.3 was added, and it was kept in in a thermostatic chamber at
37.degree. C. The polymer powder disappeared in a period of several
hours to 20 hours, and the solution in the test tube became
slightly yellow semitransparent. As in Example 1, an imide ring in
the polymer structure was hydrolyzed to produce a carboxyl group,
so that the polymer became water-soluble. While the test tube was
further allowed to stand in the thermostatic chamber as it was,
observation was continued. In consequence, after the lapse of about
12 days, the solution began to whiten, and after the lapse of about
15 days, a white precipitate was observed. This reason is that the
water-soluble aspartic acid unit was cleaved by decomposition, and
the ratio of the lactic acid unit in the polymer increased, so that
it became water-insoluble again. After the lapse of about 19 days,
the solution was centrifugally separated to collect a white
precipitate, thereby obtaining a white powder in a ratio of 25% by
weight of the polymer subjected to the test. The molecular weight
of the polymer was measured by GPC, so that an Mw and an Mw/Mn of
the polymer were 12,300 and 1.34, respectively.
EXAMPLE 3
[0114] 106.5 g (0.8 mol) of L-aspartic acid and 288.2 g (2.0 mol)
of L-lactide were placed in a glass reactor equipped with a
stirring device and a vent. In this case, a molar ratio of fed
aspartic acid to lactic acid became 1:5. The reactor was immersed
in an oil bath at 180.degree. C., followed by stirring. Lactide
having a melting point of 98.degree. C. was molten, and heating was
continued in a condition that a white powder of insoluble aspartic
acid was floating. The powder gradually disappeared in a period of
about 30 minutes to 1 hour, and the viscosity of the yellow
reaction solution rose. After 2.5 hours from the start of the
heating, the pressure in the reaction system was slowly reduced, so
that 1 mmHg was reached after 3 hours. After the heating was
further continued for 11 hours, the reactor was taken out of the
oil bath, and the reaction solution was collected and then cooled
for solidification. The resultant lightly yellowish brown
semitransparent solid was ground to obtain a powdery polymer. An Mw
and an Mw/Mn of the polymer was 26,000 and 1.32, respectively.
[0115] According to the results of NMR measurement, a composition
ratio of a unit derived from aspartic acid to the lactic acid unit
in the polymer was 1:5.0.
[0116] According to DSC measurement, the glass transition point was
shown at 52.degree. C. No absorption of heat by melting a crystal
was shown so that the polymer was noncrystalline.
EXAMPLE 4
[0117] 6.7 g (0.05 mol) of L-aspartic acid and 36.0 g (0.25 mol) of
L-lactide were placed in a glass reactor equipped with a stirring
device and a vent. In this case, a molar ratio of fed aspartic acid
to lactic acid became 1:10. The reactor was immersed in an oil bath
at 180.degree. C., followed by stirring. Lactide having a melting
point of 98.degree. C. was molten, and heating was continued in a
condition that a white powder of insoluble aspartic acid was
floating. The powder gradually disappeared in a period of about 1
hour, and the viscosity of the yellow reaction solution rose. After
2.5 hours from the start of the heating, the pressure in the
reaction system was slowly reduced, so that 1 mmHg was reached
after 3 hours. The temperature of the oil bath was lowered to
160.degree. C., and the reaction was further continued for 6 hours.
At this point, the reaction solution was sampled, and a molecular
weight was then measured. As a result, an Mw of the sample was
8,800. After the reaction was further continued for 9 hours, the
reactor was taken out of the oil bath, and the reaction solution
was collected and then cooled for solidification. The resultant
lightly yellowish brown semitransparent solid was ground to obtain
a powdery polymer. An Mw and an Mw/Mn of the polymer was 17,000 and
1.39, respectively.
[0118] After 10 g of this polymer were dissolved in 20 g of DMF,
the solution was poured into 400 ml of water, and the resultant
precipitate was then collected to thereby purify the polymer. A
purification yield was 96%. An Mw and an Mw/Mn of the purified
polymer was 17,800 and 1.35, respectively.
[0119] According to the results of NMR measurement, a composition
ratio of a unit derived from aspartic acid to the lactic acid unit
in the polymer was 1:10.4.
[0120] According to DSC measurement, the absorption of heat was
shown at 49.degree. C.
[0121] The solubilities of the polymer in various solvents were as
follows:
[0122] Completely dissolved: Dimethyl formamide, dimethyl
sulfoxide, acetone, tetrahydrofuran, acetonitrile, ethyl acetate,
chloroform and hot toluene.
[0123] Swelled (or gummed): Methanol and ethanol.
[0124] Undissolved: Water.
EXAMPLE 5
[0125] 13.3 g (0.1 mol) of L-aspartic acid and 144.1 g (1.0 mol) of
L-lactide were placed in a glass reactor equipped with a stirring
device and a vent. In this case, a molar ratio of fed aspartic acid
to lactic acid became 1:20. The reactor was immersed in an oil bath
at 180.degree. C., followed by stirring. Lactide having a melting
point of 98.degree. C. was molten, and heating was continued in a
condition that a white powder of insoluble aspartic acid was
floating. The powder gradually disappeared in a period of about 30
minutes to 1 hour, and the viscosity of the yellow reaction
solution rose. After 2.5 hours from the start of the heating, the
pressure in the reaction system was slowly reduced, so that 1 mmHg
was reached after 3 hours. After the heating was further continued
for 12 hours, the reactor was taken out of the oil bath, and the
reaction solution was collected and then cooled for solidification.
The resultant lightly yellowish brown semitransparent solid was
ground to obtain a powdery polymer. An Mw and an Mw/Mn of the
polymer was 21,000 and 1.26, respectively.
[0126] After 10 g of this polymer were dissolved in 20 g of DMF,
the solution was poured into 400 ml of water, and the resultant
precipitate was then collected to thereby purify the polymer. A
purification yield was 95%. An Mw and an Mw/Mn of the purified
polymer was 21,000 and 1.25, respectively.
[0127] According to the results of the NMR measurement, a
composition ratio of a unit derived from aspartic acid (an aspartic
acid unit and a succinimide unit) to the lactic acid unit in the
polymer was 1:19.5.
[0128] According to DSC measurement, the glass transition point was
shown at 50.degree. C. No absorption of heat by melting a crystal
was shown so that the polymer was noncrystalline.
[0129] The solubilities of the polymer in various solvents were as
follows:
[0130] Completely dissolved: Dimethyl formamide, dimethyl
sulfoxide, acetone, tetrahydrofuran, acetonitrile, ethyl acetate
and hot toluene.
[0131] Swelled (or gummed): Methanol and ethanol.
[0132] Undissolved: Water.
[0133] The obtained polymer powder was placed in five test tubes,
and a sufficient amount of a phosphoric acid buffer solution having
a pH of 7.3 was added, followed by hydrolysis was conducted in a
thermostatic chamber at 37.degree. C. The test tube was picked up
one by one after passed one day, 5 days, 9 days, 19 days and 31
days, and insoluble polymer powder was collected from the test tube
by centrifugally separation, and then they were dried. The weight
of polymers collected, after passed one day, 5 days, 9 days, 19
days and 31 days, were 63%, 61%, 70%, 75% and 45% respectively, and
Mw were 24000, 26000, 34000, 17000 and 9000 respectively.
Comparative EXAMPLE 1
[0134] Into a glass reactor equipped with a stirring device and a
vent, 200 g of 90% aqueous solution of Laspartic acid was placed,
and the reactor was immersed in an oil bath at 180.degree. C.,
followed by stirring. When distilling water was almost finished,
the pressure in the reaction system was slowly reduced (20 mmHg).
After the heating was further continued for 5 hours, the reactant
was sampled in a little amount. The sample was a millet jelly-like
oligomer having Mw of 9500 and glass transition point of 18.degree.
C. Furthermore, under the reduced pressure (20 mmHg), the reaction
was continued at 160.degree. C. After 20 hours passed, the reactor
was taken out of the oil bath, and the reaction solution was
collected and then cooled for solidification. The polymer obtained
was polylactic acid having Mw of 17000, glass transition point of
39.degree. C. and melting point of 136.degree. C.
[0135] The solubilities of the polymer in various solvents were as
follows:
[0136] Completely dissolved: Dimethyl formamide, dimethyl sulfoxide
and chloroform
[0137] Undissolved: Acetone, toluene, tetrahydrofuran,
acetonitrile, ethyl acetate, ethanol, methanol, 2-propanol and
water.
[0138] The obtained polymer powder was placed in five test tubes,
and a sufficient amount of a phosphoric acid buffer solution having
a pH of 7.3 was added, followed by hygdrolysis was conducted in a
thermostatic chamber at 37.degree. C. The test tube was picked up
one by one after passed one day, 5 days, 9 days, 19 days and 31
days, and insoluble polymer powder was collected from the test tube
by centrifugally separation, and then they were dried. The weight
of polymers collected, after passed one day, 5 days, 9 days, 19
days and 31 days, were 97%, 96%,, 92%, 92% and 90% respectively,
and Mw were 17000, 17200, 16800, 17000 and 16500 respectively.
EXAMPLE 6
[0139] 4.21 g of the polymer powder obtained in Example 1 was
suspended in 150 ml of distilled water. The pH of the resultant
suspension was 4. While the solution was stirred and the pH of the
solution was watched, a 1N aqueous sodium hydroxide solution was
slowly added dropwise thereto. Each time the aqueous sodium
hydroxide solution was added dropwise, the pH of the solution rose
from 4 to 9, and immediately it lowered to 4. As the amount of the
dropped aqueous sodium hydroxide solution increased, the return of
the pH tended to be slow. The polymer particles suspended in the
solution were gradually solubilized, and when the amount of the
dropped aqueous sodium hydroxide solution reached 0.4 g, most of
the polymer particles disappeared and the solution became slightly
yellow semitransparent. The pH of the solution was 6.2. This
solution was concentrated to dryness, and the resultant yellowish
brown solid was dissolved in methanol. Afterward, the solution was
poured into acetonitrile to bring about reprecipitation, and the
thus reprecipitated white polymer solid was then collected. An Mw
and an Mw/Mn of the obtained polymer were 9,000 and 1.2,
respectively.
[0140] In the IR spectrum of this polymer, there were observed the
absorption peaks shown in the IR spectrum of the polymer in Example
1 as well as an intensive absorption peak characterized by an amide
structure at 1620 cm.sup.<1.
EXAMPLE 7
[0141] 0.5 g of the polymer powder obtained in Example 3 was
dissolved in 5 ml of acetonitrile, and the solution was poured into
50 ml of cotton seed oil containing 0.1% of lecithin. Then, it was
stirred by a homogenizer at 15000 rpm for 3 minutes to prepare a
oil-in-oil emulsion. the pressure in the vessel containing the
emulsion was slowly reduced, and it was stirred for 2 hours at
40.degree. C. to remove acetonitrile. The oil was given back at
room temperature and atmospheric pressure. Into the oil, 25 ml of
hexane was added, and the deposited polymer particle was collected
by filtration. Furthermore, the particle was washed well and dried.
By microscope observation, it was confirmed that the polymer powder
was microsphere having diameter of about several .mu.m to several
tens .mu.m.
EXAMPLE 7
[0142] 1.5 g of the copolymer obtained in Example 5 was dissolved
in 10 ml of chloroform. A solution, in which 100 mg of
acetaminophen was dissolved in 1 ml of water, was poured into the
chloroform solution, and then, it was stirred by a homogenizer at
12000 rpm for 3 minutes to prepare an emulsion. The emulsion was
slowly dropwised by a pipette into 200 ml of 1% aqueous solution of
polyvinylalcohol (polymerization degree: about 500). The pressure
in the vessel containing the emulsion obtained was reduced to
remove chloroform. The deposited polymer particle was collected by
filtration. Furthermore, the particle was washed by water and dried
to obtain a microsphere containing a desired pharmaceutical
component.
[0143] As described above, according to the present invention,
there can be provided a novel copolymer having a succinimide unit
and/or an aspartic acid unit as well as a lactic acid unit and/or a
glycolic acid unit as repeating structural units, and a process for
preparing the copolymer. This copolymer is solid at ordinary
temperature, has a relatively low melting point, shows a specific
hydrolysis behavior, and is useful as a novel biologically
absorbable polymer, for example, as a base material for a sustained
releasing drug.
[0144] In addition, according to the preparation process of the
present invention, a novel copolymer having a high molecular weight
and a narrow molecular weight distribution can be obtained in a
high yield.
* * * * *