Drug release controlling material responsive to changes in temperature

The present invention related to a drug release controlling material responsive to changes in temperature comprising the polyester gel which is obtained by polymerization of a polyfunctional macromonomer represented by the general formula (I): ##STR1## wherein R.sup.1 represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, X.sup.1 represents a hydrogen atom, a halogen atom, a cyano group, an alkyl group having from 1 to 6 carbon atoms or a phenyl group, A represents an aliphatic polyester chain, m is 0 or 1, and p, which may be the same or different in each branched chain, represents an integer of from 0 to 6, optionally with a polyethylene glycol derivative which contains polymerizable group(s) at the end(s). The drug release controlling material has an on-off control function of drug release responsive to changes in temperature depending upon the gel transition of the aliphatic polyester gel.

FIELD OF THE INVENTION 
The present invention relates to a material for controlling a drug release 
responsive to changes in temperature, which comprises a polyester gel 
obtained by polymerization of a polyfunctional macromonomer which contains 
an aliphatic polyester chain as a main component and which contains 3 to 4 
polymerizable substituents, optionally with a polyethylene glycol 
derivative which contains polymerizable group(s) at the end(s). 
The polyester gel of the present invention makes it possible to control its 
thermal transition temperature by varying constituting components of the 
aliphatic polyester chain as a main component or the average 
polymerization degree thereof and, therefore, is useful as a material 
which can be used for an on-off control of drug release in any desired 
temperature range. 
BACKGROUND OF THE INVENTION 
Recently, a new technique for drug administration has recently been studied 
for the purpose of effectively-delivering a drug to a target portion 
thereby reducing possible side-effects, i.e., the drug delivery system 
(DDS). In particular, application of polymers which undergo changes in 
chemical structure, phase transition, and changes in shape and physical 
properties responsive to changes in surrounding conditions caused by, for 
example, a chemical substance, pH, temperature, electric or magnetic 
field, to a timing control of drug release is actively studied. By using a 
pharmaceutical preparation comprising such stimulus-responsive high 
molecular weight compounds, a drug delivery system having various 
functions can be obtained. For example, the pharmaceutical preparation per 
se notices a signal generated from physiological changes in the living 
body, determines an amount of the drug to be released depending upon the 
degree of physiological changes, and releases the drug or stops the drug 
release (on-off controlling function). 
In particular, a temperature-sensitive drug releasing system using a 
polymeric material responsive to changes in temperature is capable of 
releasing the drug when required, for example, by releasing an antipyretic 
agent only when a patient has fever or external heat is applied, and is 
extensively studied as a practical DDS. The polymeric materials which have 
been proposed thus far and which respond to changes in temperature include 
a gel comprising poly-N-isopropylacrylamide as described in, for example, 
Okano et al., Hyomen (Surface Science), Vol. 10, p. 90, 1989, and J. 
Controlled Release, Vol. 11, p. 255, 1990; a gel comprising a copolymer of 
N-isopropylacrylamide and an alkyl methacrylate as described in, for 
example, Yoshida et al., Jinko Zoki (Artificial Organs), Vol. 19, p. 1243, 
1990, and Drug Delivery System, Vol. 5, p. 279, 1990; an interpenetrating 
polymer network (IPN) gel comprising polyacrylic acid and polyacrylamide 
as described in, for example, Katono et al., J. Controlled Release, Vol. 
16, p. 215, 1991; and a film comprising a porous film impregnated with 
liquid crystal molecules as described in, for example, Nozawa et al., J. 
Controlled Release, Vol. 15, p. 29, 1991. With these polymeric materials, 
the on-off control of the drug release responsive to changes in 
temperature is put into practical use by utilizing shrinking or swelling 
of gel depending upon changes in temperature, or by utilizing difference 
in permeability at a temperature just below or above the liquid crystal 
transition temperature. 
However, the conventional polymers which respond to changes in temperature, 
that is, so-called temperature-responsive polymers, have various 
disadvantages such that they have poor mechanical strength, the 
temperature for the on-off control can not be optionally set, the polymers 
remain unchanged when used in the living body. In the case-of liquid 
crystal impregnated film, the liquid crystal molecule can not be fixed 
sufficiently and, therefore, the film is unstable in repeated use. For the 
reasons described above, the conventional temperature-responsive polymers 
have not yet been put into practical use. In particular, since the on-off 
control of the drug release is mostly performed in the living body, it is 
highly desirable to use a material which can be degraded and absorbed in 
the living body or under natural environmental conditions. However, it has 
not been proposed to use the biodegradable polymer as a 
temperature-responsive polymer. 
As a result of extensive studies, the present inventors have found a novel 
temperature-responsive polymer which is degraded and absorbed in the 
living body or under natural environmental conditions after use and also 
which is free from problems associated with the conventional materials 
such that the materials have poor mechanical strength and are difficult to 
optionally set the temperature at which the on-off control is performed. 
The novel polymer can be produced by using a polymer which mainly 
comprises aliphatic polyesters such as polylactide, polyglycollide, 
poly-.gamma.-butyrolactone, poly-.epsilon.-caprolactone, 
poly-.beta.-hydroxybutyric acid and poly-.beta.-hydroxyvaleric acid which 
are known as biodegradable polymers as described in Kobunshi Shin-sozai 
Binran (Bulletin of Polymeric New Materials), edited by the Society of 
Polymer Science, Japan, 1989, pp. 322-347, and completed the present 
invention. 
SUMMARY OF THE INVENTION 
The object of the present invention is therefore to provide a novel 
temperature-responsive polymeric material mainly comprising a 
biodegradable polymeric material having mechanical properties suitable for 
use in various utilities, in particular, a high tensile elongation, by 
forming a three-dimensional crosslinked material, i.e., gel, which 
comprises, as a main component, a polymeric chain composed of an aliphatic 
polyester such as polylactide, polyglycollide, polylactones and 
poly-.beta.-hydroxyalkanoate or copolymers thereof. 
The polyester gel possesses mechanical properties suitable to various 
utilities, in particular, as a biodegradable polymeric material having a 
high tensile elongation. The gel can be provided with any desirable 
mechanical properties and gel transition temperatures by varying 
constituting components of the aliphatic polyester chain as a main 
component and average polymerization degree of the gel. The drug release 
controlling material has an on-off control function of drug release 
responsive to changes in temperature depending upon the gel transition of 
the aliphatic polyester gel, i.e., just below or above the transition 
temperature of the gel.

DETAILED DESCRIPTION OF THE INVENTION 
The drug release controlling material responsive to changes in temperature 
comprises a polyester gel obtained by polymerization of a polyfunctional 
macromonomer represented by the general formula (I): 
##STR2## 
wherein R.sup.1 represents a hydrogen atom or an alkyl group having from 1 
to 6 carbon atoms, X.sup.1 represents a hydrogen atom, a halogen atom, a 
cyano group, an alkyl group having from 1 to 6 carbon atoms or a phenyl 
group, A represents an aliphatic polyester chain, m is 0 or 1, and p, 
which may be the same or different in each branched chain, represents an 
integer of from 0 to 6. 
The aliphatic chain represented by A in the above general formula (I) is, 
preferably, composed of a repeating unit represented by the general 
formula (II): 
##STR3## 
wherein R.sup.2 which may be the same or different in each repeating unit, 
represents a hydrogen atom, a methyl group or an ethyl group, and q, which 
may be the same or different in each repeating unit, represents an integer 
of from 0 to 6, and is characterized by having an average polymerization 
degree in the range of from 5 to 500. 
The present invention also includes a drug release controlling material 
responsive to changes in temperature comprises a polyester gel obtained by 
polymerization of a polyfunctional macromonomer represented by the general 
formula (I): 
##STR4## 
wherein R.sup.1 represents a hydrogen atom or an alkyl group having from 1 
to 6 carbon atoms, X represents a hydrogen atom, a halogen atom, a cyano 
group, an alkyl group having from 1 to 6 carbon atoms or a phenyl group, A 
represents an aliphatic polyester chain, m is 0 or 1, and p, which may be 
the same or different in each branched chain, represents an integer of 
from 0 to 6, and a polyethylene glycol derivative represented by the 
general formula (III): 
##STR5## 
wherein X.sup.2 represents a hydrogen atom, a halogen atom, a cyano group, 
an alkyl group having from 1 to 6 carbon atoms or a phenyl group, Y 
represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms 
or a group represented by --C(.dbd.O)C(X.sup.2).dbd.CH.sub.2, n represents 
an integer of from 5 to 50, after mixing them in a ratio of the compound 
represented by the formula (I)/the polyethylene glycol derivative ranging 
from 99/1 to 70/30 by weight. 
The polyester polyfunctional macromonomer represented by the above general 
formula (I) according to the present invention can be easily prepared by, 
for example, ring-opening polymerization of a cyclic ester compound 
represented by the general formula (IV): 
##STR6## 
wherein R.sup.2 is as defined above, or the general formula (V): 
##STR7## 
wherein R.sup.2 and q are as defined above, or a mixture thereof, in the 
presence of a triol or tetraol compound represented by the general formula 
(VI): 
##STR8## 
wherein R.sup.1, m and p are as defined above, to obtain a precursor 
represented by the general formula (VII): 
##STR9## 
wherein R.sup.1 A, m and p are as defined above, and reacting the 
resulting precursor with an acid chloride represented by the general 
formula (VIII): 
##STR10## 
wherein X.sup.1 is as defined above. 
Examples of the triol or tetraol compound represented by the general 
formula (VI) used above include glycerin, 1,1,1-tri(hydroxymethyl) ethane, 
1,1,1-tri (hydroxymethyl)propane, 1,1,1-tri(hydroxymethyl)butane, 
1,1,1-tri(hydroxymethyl)pentane, 1,1,1-tri(hydroxymethyl) hexane, 1, 
1,1-tri (hydroxymethyl) heptane, pentaerythritol, 1,3,5-tri 
(hydroxymethyl) pentane, 1,3,3,5-tetra(hydroxymethyl)pentane, 1,2, 
6-trihydroxyhexane and 1,2,2,6-tetrahydroxyhexane. 
Examples of the cyclic ester compound represented by the general formula 
(IV) or (V) include glycollide, D,L-lactide, L-lactide, D-lactide, 
.beta.-propiolactone, .beta.-butyrolactone, .gamma.-butyrolactone, 
.beta.-valerolactone, .gamma.-valerolactone, .delta.-valerolactone, 
.gamma.-caprolactone, .delta.-caprolactone and .epsilon.-caprolactone. 
These cyclic ester compounds can be used singly or as a mixture thereof, 
and by heating the cyclic ester compound at a temperature of from 
50.degree. C. to 200 .degree. C., preferably from 100 .degree. C. to 200 
.degree. C., in the presence of the triol or tetraol compound represented 
by the general formula (VI), the ring-opening polymerization proceeds 
easily to obtain the precursor represented by the general formula (VIII) 
above. When the ring-opening polymerization is performed using a lactide, 
a catalyst is preferably used. Examples of the catalyst which can be used 
include tin type catalysts, such as tin 2-ethylhexanoate, tributyltin 
acetate, tributyltin chloride, methoxytributyltin and t-butoxytributyltin; 
antimony type catalysts such as antimony trioxide, antimony trichloride, 
antimony pentachloride and antimony trifluoride; and zinc type catalysts 
such as zinc powder, zinc oxide, zinc acetate, zinc chloride and zinc 
fluoride. 
Examples of the acid chloride represented by the general formula (VIII) 
which can be used for producing the polyester polyfunctional macromonomer 
represented by the general formula (I) of the present invention from the 
thus-produced precursor represented by the general formula (VII) above 
include acryloyl chloride, .alpha.-chloroacryloyl chloride, 
.alpha.-cyanoacryloyl chloride, methacryloyl chloride, 
.alpha.-butylacryloyl chloride and .alpha.-phenylacryloyl chloride. The 
reaction between the precursor of the general formula (VII) and the acid 
chloride of the general formula (VIII) is preferably carried out in an 
organic solvent. Examples of preferred organic solvents include 
tetrahydrofuran, benzene, toluene, chloroform, carbon tetrachloride, 
N,N-dimethylformamide, dimethyl sulfoxide, and the like. Since hydrogen 
chloride is generated during the reaction, the reaction is preferably 
conducted in the presence of an organic base such as triethylamine, 
N,N-dimethylaniline and pyridine as a scavenger of hydrogen chloride. 
The polyethylene glycol derivative represented by the formula (III) is 
partly commercially available, and may be also easily prepared by reacting 
a commercially available polyethylene glycol having hydroxyl group(s) at 
the one or both ends with an acid chloride represented by the formula 
(IX): 
##STR11## 
wherein X.sup.2 represents a hydrogen atom, a halogen atom, a cyano group, 
an alkyl group having from 1 to 6 carbon atoms or a phenyl group. 
In producing the polyester gel of the present invention by polymerization 
of the polyfunctional macromonomer of the general formula (I) obtained as 
above, a conventional addition polymerization method such as a radical 
polymerization, an anionic polymerization and a cationic polymerization 
can be used, with the radical polymerization being the most advantageous 
method. 
The polyester gel obtained by polymerization of a polyfunctional 
macromonomer represented by the general formula (I) and a polyethylene 
glycol derivative represented by the general formula (III) can also be 
produced similarly using the macromonomer and polyethylene glycol 
derivative as the starting monomers. The weight ratio of the macromonomer 
represented by the formula (I) to the derivative represented by the 
formula (III) ranges from 99/1 to 70/30, preferably from 95/5 to 80/20. 
The increase of the ratio of the former monomer reduces the permeation of 
a drug through the resulting gel, and on-off control relative to change in 
temperature becomes difficult when the ratio of the former monomer is too 
small. 
The radical polymerization can be carried out by a conventional procedure 
such as bulk polymerization, solution polymerization and emulsion 
polymerization method. Also, the radical polymerization can be initiated 
by merely heating, radiation with visible light or ultraviolet rays or by 
adding a radical polymerization initiator. Examples of the radical 
polymerization initiator which are preferably used in the reaction include 
organic peroxides such as dilauroyl peroxide, di-t-butyl peroxide, benzoyl 
peroxide, t-butylhydroxy peroxide and cumene hydroperoxide, or azo 
compounds such as .alpha.,.alpha.'-azobisisobutyronitrile, and 
azobiscyclohexanecarbonitrile. When the polymerization is initiated by 
radiation with visible light or ultraviolet rays, the polymerization is 
preferably initiated in the presence of conventional photo-polymerization 
initiator and a sensitizer. Examples of the photopolymerization initiator 
which can be used include benzoin, benzophenone, acetophenon, benzil, 
p,p'-dimethoxybenzil, camphorquinone, p,p'-dichlorobenzil, camphorquinone, 
.alpha.-naphthyl, acenaphthene, thioxanthone, 2-chlorothioxanthone, 
2-methylthioxanthone and 2,4-diethoxythioxanthone, 
trimethylbenzoyldiphenylphosphine oxide. Examples of the sensitizer which 
can be preferably used include n-butylamine, triethylamine, 
dimethylaminoethyl methacrylate, N,N-dimethylaniline, 
N,N-dimethyltoluidine, triethyl-n-butylphosphine, and isoamyl 
4-dimethylaminobenzoate. Examples of the organic solvent which can be used 
include benzene, toluene, xylene, chlorobenzene, tetrahydrofuran, 
chloroform, methyl ethyl ketone, fluorobenzene, methanol, ethanol, 
n-propanol, isopropanol, N,N-dimethylformamide and N,N-dimethylacetamide, 
but the solvent is not limited thereto. The polymerization reaction 
proceeds smoothly at a temperature in the range of from room temperature 
to 100.degree. C. The polymerization reaction can be carried out in a 
usual reaction vessel under stirring, but it can also be conducted by 
pouring a starting macromonomer and necessary reagents such as a solvent 
and a polymerization initiator into a space between glass plates or into a 
mold. Accordingly, the gel may be formed in any desired shape such as film 
or membrane, plate, rod, sphere, tube and pellet during the 
polymerization, and can be further subjected to a secondary processing 
such as stretching and spinning. 
As shown in the test examples described hereinafter, the thus-obtained 
polyester gel which can be used in the present invention can be provided 
with different mechanical properties such as tensile modulus, tensile 
strength and elongation percentage by changing the component in the 
repeating unit of the aliphatic polyester chain represented by A in the 
polyfunctional macromonomer or the average polymerization degree, and 
further, the gel transition temperature can be optionally controlled. In 
particular, when it is desired to conduct the on-off control depending on 
the drug-releasing temperature at a temperature in the living body, i.e., 
about from 30.degree. to about 40.degree. C. the component in the 
repeating unit of the aliphatic polyester chain represented by A in the 
polyfunctional macromonomer of the general formula (I) is desirably a 
component containing polylactone, and the average polymerization degree 
thereof is preferably in the range of from 5 to 100. Further, since the 
gel can be fabricated into any desired shapes during the polymerization of 
the macromonomer starting material as described above, it is possible to 
form a desired shape suitable to the intended utility of the material such 
as films, membranes, plates, rods, sphere, tubes, needles, threads or 
microcapsules. Thus, the polyester gel according to the present invention 
can be used for wide variety of utilities, for example, hydrolyzable or 
biodegradable plastics, rubbers or fibers, absorbable suture threads, or 
matrix for sustained release preparations of drugs such as medicines, 
agricultural agents or microcidal agents. 
In preparing preparations comprising the drug release controlling material 
according to the present invention, the drug can be incorporated into the 
gel by mixing the drug with the polyfunctional macromonomer during the 
polymerization of the macromonomer, or by impregnating the gel with the 
drug, or sealing the drug into the gel which has been shaped in the form 
of films, membranes, tubes, capsules or the like. 
The drugs used in the DDS which is responsive to changes in temperature by 
using the drug release controlling material of the present invention can 
be any type of drugs for human or animals. Examples of drugs include 
anti-inflammatory analgesic agent such as acetaminophenone, acetyl 
salicycloyl (aspirin), methyl salicylate, choline saticylate, glycol 
salicylate, 1-menthol, camphor, mefenamic acid, flufenamic acid, 
antipyrine, indomethacin, diclofenac, alclofenac, ibuprofen, ketoprofen, 
naproxen, pranoprofen, fenoprofen, fenprofen, flurbiprofen, indoprofen, 
fentiazac, tolmetin, suprofen, benzadac, bufexamac, piroxicam, 
phenylbutazone, oxyphenbutazone, clofezone, pentazocine and mepirizole; 
steroid type anti-inflammatory agents such as hydrocortisone, 
predonisolone, dexamethasone, triamcinolone acetonide, fluocinolone 
acetonide and fludorocortisone acetate; antihistamic of antiallergic 
agents such as chlorpheniramine, glycyrrhizic acid, diphenhydramine and 
periactin; local anesthetic agents such as benzocaine, procaine, dibucaine 
and lidocaine; antimicrobial agents such as tetracyclines, e.g., 
chlortetracycline, penicillins, e.g., ampicillin, cephalosporines, e.g., 
cefalotin, aminoglycosides, e.g., kanamycin, macrolides, e.g., 
erythromycin, chloramphenicol, iodine compounds, nitrofurantoin, nystatin, 
amphotericin, fradiomycin, sulfonamides, pyrrolnitrin, clotrimazole and 
nitrofurazone; antihypertensive agents such as clonidine, 
.alpha.-methyldopa, reserpine, syrosingopine, rescinnamine, cinnarizine, 
hydrazine and prazosin; hypotensive diuretic agents such as theophylline, 
trichlormethiaide, furosemide, tribamide, methylclothiazide, penflutizide, 
hydrothiazide, spironolactone and metolazone; cardiotonic agents such as 
digitalis, ubidecarenone and dopamin; coronary vasodilators such as 
nitroglycerin, isosorbitol dinitrate, erythritol tetranitrate, 
pentaerythritol tetranitrate, dipyridamole, dilazep, trapidil and 
trimetazidine; vasoconstrictors such as dihydroergotamine and 
dihydroergotoxine; .beta.-blockers or antiarrhythmic agents such as 
pindolol and propranolol; calcium antagonists such as diltiazem, 
nifedipine, nicardipine, verapamil, bencyclan and dilazep; antiepileptic 
agents such as nitrazepam, meprobamate and phenytoin; antivertigo agents 
such as isoprenaline, betahistine and scopolamine; psycholeptics such as 
diazepam, lorazepam, flunitrazepam and fluphenazine; hypnotic sedatives 
such as phenobarbital, amobarbital and cyclobarbital; muscle relaxants 
such as triperizone, baclofen, tantrolene sodium and cyclopenzaprine; 
agents for autonomic nerves such as atropine and levodopa; agents for 
respiratory organs such as codeine, ephedrine, isoproterenol, 
dextromethorphan, oleciprenatorin, ipratropium bromide and cromoglicic 
acid; hormones and antihormone agents such as corticotropin, oxytocin, 
vasopressin, testosterone, progesterone and estradiol; salivary gland 
hormones, thyroid hormones, adorenal hormones, kallikrein, insulin and 
oxendolone; vitamins A, B, C, D, E, K and their derivatives, calciferols 
and mecobalamin; antitumor agents such as 5-fluorouracil and derivatives 
thereof, adriamycin, krestin, picibanil, ancitabine and cytarabine; 
enzymes such as urokinase; herb medicines or herb extracts such 
glycyrrhiza, aloes and allantoin, aldioxa and alcloxa; and others such as 
prostaglandins, antidiabetic agents. These drugs may be used alone or in a 
combination of two or more drugs. The DDS using the drug release 
controlling material according to the present invention which is 
responsive to changes in the temperature is not limited to the use of the 
above-described drugs and can also be applied to agricultural agents such 
as insecticides, herbicides and fertilizers according to the intended 
utility. Thus, the term "drug" in the present specification and claims 
includes not only the drugs for medication but also any physiologically 
active agents such as the agricultural agents and any test or marker 
agents. Accordingly, the use of the material according to the present 
invention for controlling the release of the agricultural agents, of 
course, falls within the scope of the present invention. 
EXAMPLES 
The present invention is further illustrated by the following Referential 
Examples, Examples, and test examples, but they are not construed as 
limiting the present invention. In the following .sup.1 H-NMR spectral 
data, the symbol "H" stands for a proton assigned to its chemical shift. 
REFERENTIAL EXAMPLES 1 to 4 
##STR12## 
1, 1, 1-Tri (hydroxymethyl) propane (hereinafter abbreviated as THP) and 
.epsilon.-caprolactone (hereinafter abbreviated as CL) in amounts shown in 
Table 1 below were mixed and heated at 185.degree. C. for 3 days under 
stirring. The resulting reaction mixture was dissolved in acetone and 
reprecipitated in an excess amount of a mixed solvent of hexane/diethyl 
ether (1/1 by Volume) to obtain a precursor comprising 
poly-.epsilon.-caprolactone represented by the above chemical formula (1) 
as a while powder. 
.sup.1 H-NMR, .delta.(CDCl.sub.3, ppm); 0.88 (t, C"H".sub.3 CH.sub.2 --), 
1.58 (m, --CH.sub.2 (C"H".sub.2).sub.3 CH.sub.2)--, CH.sub.3 C"H".sub.2 
--), 2.31 (t, --COC"H".sub.2 --), 4.06 (t, --C"H".sub.2 O--). IR 
(cm.sup.-1); 3520 (--OH), 2940, 2870, 1730 (C.dbd.O), 1470, 1420, 1370, 
1300, 1240, 1190, 1110, 1050, 960, 730. 
The resulting precursor was dissolved in tetrahydrofuran, and about 7.5 
molar equivalent of methacryloyl chloride and triethylamine were added to 
the solution, followed by stirring for 3 days at room temperature. Then, 
after distilling off the solvent and unreacted methacryloyl chloride and 
triethylamine, ethyl acetate was added thereto, and the salt thus produced 
was separated by filtration. The filtrate was concentrated and 
reprecipitated in an excess amount of a mixed solvent of hexane/diethyl 
ether/methanol (18/1/1 by volume) to obtain a trifunctional macromonomer 
having a structure represented by the chemical formula (2) above as a 
white powder. An amount of the product, a yield (%), an average 
polymerization degree determined from a peak area ratio of .sup.1 H-NMR 
spectrum, and a weight-average molecular weight determined based on the 
polystyrene standards by GPC are shown in Table 1 below. 
.sup.1 H-NMR, .delta.(CDCl.sub.3, ppm); 0.88 (t, C"H".sub.3 CH.sub.2 --), 
1.58 (m, --CH.sub.2 (C"H".sub.2).sub.3 CH.sub.2 O--, CH.sub.3 C"H".sub.2 
--), 1.90 (s, --C(C"H".sub.3).dbd.CH.sub.2), 2.31 (t, -COC"H".sub.2 --), 
4.06 (t, --C"H".sub.2 O --), 5.58 (d, --C (CH.sub.3).dbd.C"H".sub.2), 6.12 
(d, --C(CH.sub.3).dbd.C"H".sub.2). IR (cm.sup.-1); 2940, 2870, 1730 
(C.dbd.O), 1640 (C.dbd.C), 1470, 1420, 1370, 1300, 1240, 1190, 1110, 1050, 
960, 840, 730. 
TABLE 1 
__________________________________________________________________________ 
Ref. Amount 
Amount Average Weight-average 
Example 
of THP 
of CL 
Yield, g 
Polymerization 
Molecular 
No. g (mmol) 
g (mmol) 
(% yield) 
Degree Weight 
__________________________________________________________________________ 
1 12.1 103 83.2 3.0 2.83 .times. 10.sup.3 
(90.2) 
(902) 
(72.3) 
2 2.00 34.0 31.9 6.1 7.49 .times. 10.sup.3 
(14.9) 
(298) 
(88.6) 
3 2.42 82.4 82.7 13.2 1.20 .times. 10.sup.4 
(18.0) 
(722) 
(97.5) 
4 0.605 
41.2 38.2 25.5 2.20 .times. 10.sup.4 
(4.51) 
(361) 
(91.5) 
__________________________________________________________________________ 
REFERENTIAL EXAMPLES 5 TO 9 
##STR13## 
Pentaerythritol (hereinafter abbreviated as PET) and CL in amounts shown in 
Table 2 below were mixed, and the mixture was heated at 185.degree. C. for 
3 days under stirring. The resulting reaction mixture was dissolved in 
acetone and reprecipitated in an excess amount of a mixed solvent of 
hexane/diethyl ether (1/1 by volume) to obtain a precursor comprising 
poly-.epsilon.-caprolactone represented by the chemical formula (3) above. 
.sup.1 H-NMR, .delta.(CDCl.sub.3, ppm); 1.58 (m, --CH.sub.2 
(C"H".sub.2).sub.3 CH.sub.2 O--), 2.31 (t, --COC"H".sub.2 --), 4.06 (t, 
--C"H".sub.2 O--). IR (cm.sup.-1); 3520 (--OH), 2940, 2870, 1730 
(C.dbd.O), 1470, 1420, 1370, 1300, 1240, 1190, 1110, 1050, 960, 730. 
The resulting precursor was dissolved in tetrahydrofuran, and about 7.5 
molar equivant of methacryloyl chloride and triethylamine were added to 
the solution, followed by stirring for 3 days at room temperature. Then, 
after distilling off the solvent and unreacted methacryloyl chloride and 
triethylamine, ethyl acetate was added thereto, and the salt thus produced 
was separated by filtration. The filtrate was concentrated and 
reprecipitated in an excess amount of a mixed solvent of hexane/diethyl 
ether/methanol (18/1/1 by volume) to obtain a tetrafunctional macromonomer 
having a structure represented by the chemical formula (4) above as a 
white powder. An amount of the product, a yield (%), an average 
polymerization degree determined from a peak area ratio of .sup.1 H-NMR 
spectrum, and a weight-average molecular weight determined based on the 
polystyrene standards by GPC are shown in Table 2 below. 
.sup.1 H-NMR, .delta.(CDCl.sub.3, ppm); 1.58 (m, --CH.sub.2 
(C"H".sub.2).sub.3 CH.sub.2 O--), 1.90 (s, --C(C"H".sub.3).dbd.CH.sub.2), 
2.31 (t, --COC"H".sub.2 --), 4.06 (t, --C"H".sub.2 O--), 5.58 (d,--C 
(CH.sub.3).dbd.C"H".sub.2), 6.12 (d, --C (CH.sub.3).dbd.C"H".sub.2). IR 
(cm.sup.-1); 2940, 2870, 1730 (C.dbd.O), 1640(C.dbd.C), 1470, 1420, 1370, 
1300, 1240, 1190, 1110, 1050, 960, 840, 730. 
TABLE 2 
__________________________________________________________________________ 
Ref. Amount 
Amount Average Weight-average 
Example 
of PET 
of CL 
Yield, g 
Polymerization 
Molecular 
No. g (mmol) 
g (mmol) 
(% yield) 
Degree Weight 
__________________________________________________________________________ 
5 12.3 103 80.9 2.3 2.78 .times. 10.sup.3 
(90.3) 
(902) 
(78.6) 
6 2.46 41.2 34.1 4.7 6.90 .times. 10.sup.3 
(18.1) 
(361) 
(78.2) 
7 2.46 82.4 83.2 9.5 1.02 .times. 10.sup.4 
(18.1) 
(722) 
(98.1) 
8 1.23 82.4 74.2 19.1 2.05 .times. 10.sup.4 
(9.03) 
(722) 
(88.7) 
9 0.398 
40.0 35.9 28.5 4.87 .times. 10.sup.4 
(2.92) 
(350) 
(88.7) 
__________________________________________________________________________ 
##STR14## 
0.233 g (1.73 mmol) of THP, 10.0 g (69.4 mmol) of D,L-lactide (hereinafter 
abbreviated as LA) and 0.05 g (0.123 mmol) of tin 2-ethylphexanoate were 
mixed, and heated at 185 .degree. C. for 20 hours under stirring. The 
reaction mixture was dissolved in acetone and reprecipitated in an excess 
amount of a mixed solvent of hexane/diethyl ether/methanol (1/1/0.05 by 
volume) to obtain a precursor comprising polylactide represented by the 
chemical formula (5) above as a white powder. 
.sup.1 H-NMR, .delta.(CDCl.sub.3, ppm); 0.89 (t, C"H".sub.3 CH.sub.2 --), 
1.54 (m, --CH(C"H".sub.3)O--), 1.60 (m, CH.sub.3 C"H".sub.2 --), 4.05 (t, 
--C"H".sub.2 O--), 5.16 (q, C"H"(CH.sub.3)O--). IR (cm.sup.-1); 3550 
(--OH), 2990, 2940, 1750 (C.dbd.O), 1450, 1380, 1260, 1190, 1130, 1090, 
1050, 950, 870, 760. 
The resulting precursor was dissolved in tetrahydrofuran, and about 7.5 
molar equivalent of methacryloyl chloride and triethylamine were added to 
the solution, followed by stirring for hours at room temperature. Then, 
after distilling off the solvent and unreacted methacryloyl chloride and 
triethylamine, ethyl acetate was added thereto, and the salt thus produced 
was separated by filtration. The filtrate was concentrated and 
reprecipitated in an excess amount of a mixed solvent of hexane/diethyl 
ether/methanol (18/1/1 by volume) to obtain a trifunctional macromonomer 
having a structure represented by the chemical formula (6) above as a 
white powder. The yield was 6.68 g (65.3% yield). Also, the average 
polymerization degree calculated from the peak area ratio of .sup.1 H-NMR 
spectrum was 12.5, and the weight-average molecular weight determined 
based on the polystyrene standards by GPC was 1.24.times.10.sup.4. 
.sup.1 H-NMR, .delta.(CDCl.sup.3, ppm); 0.89 (t, C"H".sub.3 CH.sub.2 --), 
1.54 (m, --CH(C"H".sub.3)O--), 1.60 (m, CH.sub.3 C"H".sub.2 --), 1.90 (s, 
--C(C"H".sub.3).dbd.CH.sub.2), 4.05 (t, --C"H".sub.2 O--), 5.16 (q, 
C"H"(CH.sub.3)O--), 5.58 (d, --C(CH.sub.3).dbd.C"H".sub.2), 6.12 (d, 
--(CH.sub.3).dbd.C"H".sub.2) . IR (cm.sup.-1); 2990, 2940, 1750 (C.dbd.O), 
1640 (C.dbd.C), 1450, 1380, 1260, 1190, 1130, 1090, 1050, 950, 870, 810, 
760. 
##STR15## 
0.235 g (1.73 mmol) of PET, 10.0 g (69.4 mmol) of LA and 0.05 g (0.123 
mmol) of tin 2-ethylhexanoate were mixed and heated at 185.degree. C. for 
24 hours under stirring. The resulting reaction mixture was dissolved in 
acetone and reprecipitated in an excess amount of a mixed solvent of 
hexane/diethyl ether/methanol (1/1/0.05 by volume) to obtain a precursor 
comprising a polylactide represented by the chemical formula (7) above as 
a white powder. 
.sup.1 H-NMR, .delta.(CDCl.sub.3, ppm); 1.54 (m, --CH(C"H".sub.3)O--), 4.05 
(t, --C"H".sub.2 O--), 5.16 (q, C"H"(CH.sub.3)O--) . IR (cm.sup.-1); 3550 
(--OH), 2990, 2940, 1750 (C.dbd.O), 1450, 1380, 1260, 1190, 1130, 1090, 
1050, 950, 870, 760. 
The resulting precursor was dissolved in tetrahydrofuran, and about 10 
molar equivalent of methacryloyl chloride and triethylamine were added to 
the solution, followed by stirring for 3 days at room temperature. Then, 
after distilling off the solvent and unreacted methacryloyl chloride and 
triethylamine, ethyl acetate was added thereto, and the salt thus produced 
was separated by filtration. The filtrate was concentrated and 
reprecipitated in an excess amount of a mixed solvent of hexane/diethyl 
ether/methanol (18/1/1 by volume) to obtain a tetrafunctional macromonomer 
having a structure represented by the chemical formula (8) above as a 
white powder. The yield was 7.87 g (76.9% yield). Also, the average 
polymerization degree calculated from the peak area ratio of .sup.1 H-NMR 
spectrum was 9.4, and the weight-average molecular weight determined based 
on the polystyrene standards by GPC was 1.16.times.10.sup.4. 
.sup.1 H-NMR, .delta.(CDCl.sub.3, ppm); 1.54 (m, --CH(C"H".sub.3)O--), 1.90 
(s, --C(C"H".sub.3).dbd.CH.sub.2), 4.05 (t, --C"H".sub.2 O--), 5.16 (q, 
C"H"(CH.sub.3)O--), 5.58 (d, --C (CH.sub.3).dbd.C"H".sub.2), 6.12 (d, --C 
(CH.sub.3).dbd.C"H".sub.2) . IR (cm.sup.-1); 2990, 2940, 1750 (C.dbd.O), 
1640 (C.dbd.C), 1450, 1380, 1260, 1190, 1130, 1090, 1050, 950, 870, 810, 
760. 
##STR16## 
PET and L-lactide (hereinafter abbreviated as LLA) in amounts shown in 
Table 3 below and 0.05 g (0.123 mmol) of tin 2-ethylhexanoate were mixed 
and heated at 185.degree. C. for 24 hours under stirring. The resulting 
reaction mixture was dissolved in acetone and reprecipitated in an excess 
amount of a mixed solvent of hexane/diethyl ether/methanol (1/1/0.05 by 
volume) to obtain a precursor comprising poly-L-lactide represented by the 
chemical formula (9) above as a white powder. 
.sup.1 H-NMR, .delta.(CDCl.sub.3, ppm); 1.52 (m, --CH (C"H".sub.3) O--), 
4.05 (t, --C"H"20--), 5.14 (q, C"H"(CH.sub.3)O--) . IR (cm.sup.-1); 3550 
(--OH), 2990, 2940, 1760 (C.dbd.O), 1720, 1450, 1380, 1360, 1270, 1190, 
1130, 1100, 1050, 870, 760. 
Each of the resulting precursors was dissolved in tetrahydrofuran, and 
about 10 molar equivalent of methacryloyl chloride and triethylamine were 
added to the solution, followed by stirring for 3 days at room 
temperature. Then, after distilling off the solvent and unreacted 
methacryloyl chloride and triethylamine, ethyl acetate was added thereto, 
and the salt thus produced was separated by filtration. The filtrate was 
concentrated and reprecipitated in an excess amount of a mixed solvent of 
hexane/diethyl ether/methanol (18/1/1 by volume) to obtain a 
tetrafunctional macromonomer having a structure represented by the 
chemical formula (10) above as a white powder. An amount of the product, a 
yield (%), an average polymerization degree determined from a peak area 
ratio of .sup.1 H-NMR spectrum, and a weight-average molecular weight 
determined based on the polystyrene standards by GPC are shown in Table 3 
below. 
.sup.1 H-NMR, .delta.(CDCl.sub.3, ppm); 1.54 (m, --CH(C"H".sub.3)O--), 1.90 
(s, --C(C"H".sub.3).dbd.CH.sub.2), 4.05 (t, --C"H".sub.2 O--), 5.16 (q, 
C"H"(CH.sub.3)O--), 5.58 (d, --C (CH.sub.3).dbd.C"H".sub.2), 6.12 (d, 
--C(CH.sub.3).dbd.C"H".sub.2). IR (cm.sup.-1); 2990, 2940, 1760 (C.dbd.O), 
1720, 1640 (C.dbd.C), 1450, 1380, 1360, 1270, 1190, 1130, 1090, 1050, 870, 
810, 760. 
TABLE 3 
__________________________________________________________________________ 
Ref. Amount 
Amount Average Weight-average 
Example 
of PET 
of LLA 
Yield, g 
Polymerization 
Molecular 
No. g (mmol) 
g (mmol) 
(% yield) 
Degree Weight 
__________________________________________________________________________ 
12 1.89 20.0 19.2 4.8 3.75 .times. 10.sup.3 
(13.8) 
(138) 
(87.7) 
13 0.945 
20.0 17.7 9.5 7.98 .times. 10.sup.3 
(6.94) 
(138) 
(84.5) 
14 0.472 
20.0 18.9 18.8 1.27 .times. 10.sup.4 
(3.47) 
(138) 
(92.3) 
__________________________________________________________________________ 
##STR17## 
PET, CL and LA in amounts shown in Table 4 below were mixed and heated at 
185.degree. C. for 3 days under stirring. The resulting reaction mixture 
was dissolved in acetone and reprecipitated in an excess amount of a mixed 
solvent of hexane/diethyl ether/methanol (1/1/0.05 by volume) to obtain a 
precursor comprising a CL/LA random copolymer represented by the chemical 
formula (11) above as a white powder. 
.sup.1 H-NMR, .delta.(CDCl.sub.3, ppm); 1.52 (m, --CH.sub.2 
(C"H".sub.2).sub.3 CH.sub.2 O--, --CH(C"H".sub.3)O--), 2.31 (t, 
--COC"H".sub.2 --), 4.12 (t, --C"H".sub.2 O--), 5.15 (q, 
C"H"(CH.sub.3)O--). IR (cm.sup.-1); 3490 (--OH), 2960, 2890, 1740 
(C.dbd.O), 1460, 1370, 1270, 1200, 1170, 1140, 1100, 1050, 970, 870, 750. 
The resulting precursor was dissolved in tetrahydrofuran, and about 10 
molar equivalent of methacryloyl chloride and triethylamine were added to 
the solution, followed by stirring for 3 days at room temperature. Then, 
after distilling off the solvent and unreacted methacryloyl chloride and 
triethylamine, ethyl acetate was added thereto, and the salt thus produced 
was separated by filtration. The filtrate was concentrated and 
reprecipitated in an excess amount of a mixed solvent of hexane/diethyl 
ether/methanol (18/1/1 by volume) to obtain a tetrafunctional macromonomer 
having a structure represented by the chemical formula (12) above as a 
white powder. An amount of the product, a yield (%), an average 
polymerization degree determined from a peak area ratio of .sup.1 H-NMR 
spectrum, and a weight-average molecular weight determined based on the 
polystyrene standards by GPC are shown in Table 4 below. 
.sup.1 H-NMR, .delta.(CDCl.sub.3, ppm); 1.52 (m, --CH.sub.2 (C"H".sub.2) 
.sub.3 CH.sub.2 --, --CH(C"H".sub.3)O--), 1.90 (s, 
--C(C"H".sub.3).dbd.CH.sub.2) , 2.31 (t, --COC"H".sub.2 --), 4.12 (t, 
--C"H".sub.2 O--), 5.16 (q, C"H"(CH.sub.3)O--), 5.58 (d, 
--C(CH.sub.3).dbd.C"H".sub.2), 6.11 (d, --C (CH.sub.3).dbd.C"H".sub.2). IR 
(cm.sup.-1); 2960, 2890, 1740 (C.dbd.O), 1640 (C.dbd.C), 1460, 1370, 1270, 
1200, 1170, 1140, 1100, 1050, 970, 870, 810, 750 . 
TABLE 4 
__________________________________________________________________________ 
Average 
Weight- 
Ref. Amount 
Amount 
Amount Composition 
Polymeri- 
average 
Example 
of PET 
of CL 
of LA 
Yield, g 
a/b zation 
Molecular 
No. g (mmol) 
g (mmol) 
g (mmol) 
(% yield) 
mol % Degree 
Weight 
__________________________________________________________________________ 
15 0.945 
7.83 16.0 23.4 42/58 8.8 9.47 .times. 10.sup.3 
(6.94) 
(68.6) 
(111) 
(97.9) 
16 0.945 
31.3 4.00 35.6 91/9 9.5 1.01 .times. 10.sup.4 
(6.94) 
(274) 
(27.7) 
(98.3) 
__________________________________________________________________________ 
##STR18## 
PET, CL and LLA in amounts shown in Table 5 below and 0.05 g (0.123 mmol) 
of tin 2-ethylhexanoate were mixed, and heated at 185 .degree. C. for 3 
days under stirring. The resulting reaction mixture was dissolved in 
acetone and reprecipitated in an excess amount of a mixed solvent of 
hexane/diethyl ether/methanol (1/1/0.5 by volume) to obtain a precursor 
comprising a CL/LLA random copolymer represented by the chemical formula 
(13) above. .sup.1 H-NMR, .delta.(CDCl.sub.3, ppm); 1.54 (m, --CH.sub.2 
(C"H".sub.2).sub.3 CH.sub.2 O--, --CH(C"H".sub.3)O--), 2.31 (t, 
--COC"H".sub.2 --), 4.13 (t, --C"H".sub.2 O--), 5.14 (q, 
C"H"(CH.sub.3)O--). IR (cm.sup.-1); 3530 (--OH), 2960, 2900, 1750 
(C.dbd.O), 1460, 1380, 1360, 1270, 1200, 1170, 1140, 1100, 1050, 970, 870, 
750. 
The resulting precursor was dissolved in tetrahydrofuran, and about 10 
molar equivalent of methacryloyl chloride and triethylamine were added to 
the solution, followed by stirring for 24 hours at room temperature. Then, 
after distilling off the solvent and unreacted methacryloyl chloride and 
triethylamine, ethyl acetate was added thereto, and the salt thus produced 
was separated by filtration. The filtrate was concentrated and 
reprecipitated in an excess amount of a mixed solvent of hexane/diethyl 
ether/methanol (18/1/1 by volume) to obtain a tetrafunctional macromonomer 
having a structure represented by the chemical formula (14) above as a 
white powder. An amount of the product, a yield (%), an average 
polymerization degree determined from a peak area ratio of .sup.1 H-NMR 
spectrum, and a weight-average molecular weight determined based on the 
polystyrene standards by GPC are shown in Table 5 below. 
.sup.1 H-NMR, .delta.(CDCl.sub.3, ppm); 1.54 (m, --CH.sub.2 
(C"H".sub.2).sub.3 CH.sub.2 O--, --CH(C"H".sub.3)O--), 1.96 (s, 
--C(C"H".sub.3).dbd.CH.sub.2), 2.31 (t, --COC"H".sub.2 --), 4.13 (t, 
--C"H".sub.2 O--), 5.14 (q, C"H"(CH.sub.3)O--) 5.63 (d, 
--C(CH.sub.3).dbd.C"H".sub.2), 6.12 (d, --C(CH.sub.3).dbd.C"H".sub.2). IR 
(cm.sup.-1); 2960, 2900, 1750 (C.dbd.O), 1640 (C.dbd.C), 1460, 1420, 1380, 
1360, 1270, 1200, 1170, 1140, 1100, 1050, 960, 870, 820, 750. 
TABLE 5 
__________________________________________________________________________ 
Average 
Weight- 
Ref. Amount 
Amount 
Amount Composition 
Polymeri- 
average 
Example 
of PET 
of CL 
of LLA 
Yield, g 
a/b zation 
Molecular 
No. g (mmol) 
g (mmol) 
g (mmol) 
(% yield) 
mol % Degree 
Weight 
__________________________________________________________________________ 
17 0.945 
7.83 16.0 19.4 31/69 4.8 6.7 .times. 10.sup.3 
(6.94) 
(55.5) 
(111) 
(78.4) 
18 0.945 
15.8 10.0 22.8 42/58 7.3 7.05 .times. 10.sup.3 
(6.94) 
(139) 
(69.4) 
(85.1) 
19 0.945 
31.3 4.00 35.8 86/14 9.3 1.36 .times. 10.sup.4 
(6.94) 
(222) 
(27.7) 
(98.7) 
__________________________________________________________________________ 
##STR19## 
PET and LLA in amounts shown in Table 6 below and 0.05 g (0.123 mmol) of 
tin 2-ethylhexanoate were mixed and heated at 185.degree. C. for 24 hours 
under stirring. Then, in an amount shown in Table 6 below was added to the 
resulting reaction solution, and the mixture was further heated at 185 
.degree. C. for 24 hours under stirring. The resulting reaction mixture 
was dissolved in acetone and reprecipitated in an excess amount of a mixed 
solvent of hexane/diethyl ether/methanol (1/1/0.01 by volume) to obtain a 
precursor comprising a LLA/CL block copolymer represented by the chemical 
formula (15) above as a white powder. 
.sup.1 H-NMR, .delta.(CDCl.sub.3, ppm); 1.54 (m, --CH.sub.2 
(C"H".sub.2).sub.3 CH.sub.2 O--, --CH(C"H".sub.3)O--), 2.31 (t, 
--COC"H".sub.2 --), 4.06 (t, --C"H".sub.2 O--), 5.14 (q, 
C"H"(CH.sub.3)O--). IR (cm.sup.-1); 3510 (--OH), 2940, 2870, 1730 
(C.dbd.O), 1460, 1420, 1380, 1360, 1250, 1190, 1130, 1090, 1040, 960, 870, 
740. 
The resulting precursor was dissolved in tetrahydrofuran, and about 10 
molar equivalent of methacryloyl chloride and triethylamine were added to 
the solution, followed by stirring for 24 hours at room temperature. Then, 
after distilling off the solvent and unreacted methacryloyl chloride and 
triethylamine, ethyl acetate was added thereto, and the salt thus produced 
was separated by filtration. The filtrate was concentrated and 
reprecipitated in an excess amount of a mixed solvent of hexane/diethyl 
ether/methanol (18/1/1 by volume) to obtain a tetrafunctional macromonomer 
having a structure represented by the chemical formula (16) above as a 
white powder. An amount of the product, a yield (%), an average 
polymerization degree determined from a peak area ratio of .sup.1 H-NMR 
spectrum, and a weight-average molecular weight determined based on the 
polystyrene standards by GPC are shown in Table 6 below. 
.sup.1 H-NMR, .delta.(CDCl.sub.3, ppm); 1.54 (m, --CH.sub.2 
(C"H".sub.2).sub.3 CH.sub.2 O --, --CH(C"H".sub.3)O--), 1.96 (s, 
--C(C"H".sub.3).dbd.CH.sub.2), 2.31 (t, --COC"H".sub.2 --), 4.06 (t, 
--C"H".sub.2 O--), 5.14 (q, C"H"(CH.sub.3)O--) , 5.63 (d, --C 
(CH.sub.3).dbd.C"H".sub.2) , 6.12 (d, --C(CH.sub.3).dbd.C"H".sub.2). IR 
(cm.sup.-1); 2940, 2870, 1740 (C.dbd.O), 1640 (C.dbd.C), 1460, 1420, 1380, 
1250, 1190, 1130, 1110, 1040, 960, 870, 810, 740. 
TABLE 6 
__________________________________________________________________________ 
Average 
Weight- 
Ref. Amount 
Amount 
Amount Composition 
Polymeri- 
average 
Example 
of PET 
of LLA 
of CL 
Yield, g 
a/b zation 
Molecular 
No. g (mmol) 
g (mmol) 
g (mmol) 
(% yield) 
mol % Degree 
Weight 
__________________________________________________________________________ 
20 0.189 
2.00 3.13 4.11 42/58 8.5 1.07 .times. 10.sup.4 
(1.39) 
(13.9) 
(27.4) 
(80.2) 
21 0.113 
1.20 3.75 4.56 21/79 13.2 1.58 .times. 10.sup.4 
(0.833) 
(8.33) 
(32.9) 
(92.0) 
22 0.456 
4.83 30.6 33.0 20/80 23.8 2.34 .times. 10.sup.4 
(0.486) 
(4.86) 
(38.3) 
(89.8) 
23 0.0946 
2.00 3.13 4.87 42/58 23.2 1.94 .times. 10.sup.4 
(0.695 
(13.9) 
(27.4) 
(96.8) 
24 0.0473 
2.00 3.13 4.36 47/53 37.3 2.24 .times. 10.sup.4 
(0.347) 
(13.9) 
(27.4) 
(85.6) 
25 0.199 
2.10 20.0 19.9 14/86 34.3 4.58 .times. 10.sup.4 
(1.46) 
(14.6) 
(175) 
(89.5) 
26 0.199 
4.21 20.0 20.5 25/75 38.8 4.08 .times. 10.sup.4 
(1.46) 
(29.2) 
(175) 
(84.2) 
__________________________________________________________________________ 
##STR20## 
PET and .delta.-valerolactone (hereinafter abbreviated as VL) in amounts 
shown in Table 7 below were mixed and heated at 185.degree. C. for 3 days 
under stirring. The resulting reaction mixture was dissolved in acetone 
and reprecipitated in an excess amount of a mixed solvent of 
hexane/diethyl ether (1/1 by volume) to obtain a precursor comprising a 
poly-.delta.-valerolactone represented by the chemical formula (17) above 
as a white powder. 
.sup.1 H-NMR, .delta.(CDCl.sub.3, ppm); 1.58 (m, --CH.sub.2 
(C"H".sub.2).sub.2 CH.sub.2 O--), 2.31 (t, COC"H".sub.2 --), 4.05 (t, 
--C"H".sub.2 O--). IR (cm.sup.-1); 3520 (--OH) , 2960, 2890, 1730 
(C.dbd.O), 1470, 1420, 1400, 1380, 1320, 1260, 1190, 1170, 1100, 1070, 
1050, 950, 920, 730. 
The resulting precursor was dissolved in tetrahydrofuran, and about 10 
molar equivalent of methacryloyl chloride and triethylamine were added to 
the solution, followed by stirring for 3 days at room temperature. Then, 
after distilling off the solvent and unreacted methacryloyl chloride and 
triethylamine, ethyl acetate was added thereto, and the salt thus produced 
was separated by filtration. The filtrate was concentrated and 
reprecipitated in an excess amount of a mixed solvent of hexane/diethyl 
ether/methanol (18/1/1 by volume) to obtain a tetrafunctional macromonomer 
having a structure represented by the chemical formula (18) above as a 
white powder. An amount of the product, a yield (%), an average 
polymerization degree determined from a peak area ratio of .sup.1 H-NMR 
spectrum, and a weight-average molecular weight determined based on the 
polystyrene standards by GPC are shown in Table 7 below. 
.sup.1 H-NMR, .delta.(CDCl.sub.3, ppm); 1.58 (m, --CH.sub.2 
(C"H".sub.2).sub.2 CH.sub.2 O--) , 1.90 (s, --C(C"H".sub.3).dbd.CH.sub.2), 
2.31 (t, --COC"H".sub.2 --), 4.06 (t, --C"H".sub.2 O--), 5.58 (d, 
--C(CH.sub.3).dbd.C"H".sub.2), 6.12 (d, --C(CH.sub.3).dbd.C"H".sub.2). IR 
(cm.sup.-1); 2960, 2890, 1730 (C.dbd.O), 1640 (C.dbd.C), 1470, 1420, 1400, 
1380, 1320, 1260, 1190, 1170, 1100, 1070, 1050, 950, 920, 810, 730. 
TABLE 7 
__________________________________________________________________________ 
Ref. Amount 
Amount Average Weight-average 
Example 
of PET 
of VL 
Yield, g 
Polymerization 
Molecular 
No. g (mmol) 
g (mmol) 
(% yield) 
Degree Weight 
__________________________________________________________________________ 
27 0.102 
3.00 2.52 9.5 3.00 .times. 10.sup.4 
(0.749) 
(30.0) 
(81.1) 
28 0.051 
3.00 2.43 19.5 6.18 .times. 10.sup.4 
(0.374) 
(30.0) 
(79.6) 
29 0.340 
30.0 28.8 28.8 9.00 .times. 10.sup.4 
(2.50) 
(300) 
(94.9) 
__________________________________________________________________________ 
##STR21## 
PET, CL and VL in amounts shown in Table 8 below were mixed and heated at 
185.degree. C. for 3 days under stirring. The resulting reaction mixture 
was dissolved in acetone and reprecipitated in an excess amount of a mixed 
solvent of hexane/diethyl ether (1/1 by volume) to obtain a precursor 
comprising a CL/VL random copolymer represented by the chemical formula 
(19) above as a white powder. .sup.1 H-NMR, .delta.(CDCl.sub.3, ppm); 1.58 
(m, --CH.sub.2 (C"H".sub.2).sub.3 CH.sub.2 O--, CH.sub.2 
(C"H".sub.2).sub.2 CH.sub.2 O --) , 2.30 (t, --COC"H".sub.2 --) , 4.11 (t, 
--C"H".sub.2 O--). IR (cm.sup.-1); 3520 (--OH), 2940, 2870, 1730 
(C.dbd.O), 1470, 1440, 1420, 1390, 1300, 1240, 1190, 1170, 1100, 1060, 
1040, 960, 930, 730. 
The resulting precursor was dissolved in tetrahydrofuran, and about 10 
molar equivalent of methacryloyl chloride and triethylamine were added to 
the solution, followed by stirring for days at room temperature. Then, 
after distilling off the solvent and unreacted methacryloyl chloride and 
triethylamine, ethyl acetate was added thereto, and the salt thus produced 
was separated by filtration. The filtrate was concentrated and 
reprecipitated in an excess amount of a mixed solvent of hexane/diethyl 
ether/methanol (18/1/1 by volume) to obtain a tetrafunctional macromonomer 
having a structure represented by the chemical formula (20) above as a 
white powder. An amount of the product, a yield (%), an average 
polymerization degree determined from a peak area ratio of .sup.1 H-NMR 
spectrum, and a weight-average molecular weight determined based on the 
polystyrene standards by GPC are shown in Table 8 below. 
.sup.1 H-NMR, .delta.(CDCl.sub.3, ppm); 1.58 (m, --CH.sub.2 
(C"H".sub.2).sub.3 CH.sub.2 O--, CH.sub.2 (C"H".sub.2).sub.2 CH.sub.2 --), 
1.90 (s, --C(C"H".sub.3).dbd.CH.sub.2), 2.31 (t, --COC"H".sub.2 --), 4.12 
(t, --C"H".sub.2 O--), 5.16 (q, C"H"(CH.sub.3)O--), 5.58 (d, 
--C(CH.sub.3).dbd.C"H".sub.2), 6.11 (d, --C(CH.sub.3).dbd.C"H".sub.2). IR 
(cm.sup.-1); 2940, 2870, 1730 (C.dbd.O), 1640 (C.dbd.C), 1470, 1440, 1420, 
1390, 1300, 1240, 1190, 1170, 1100, 1060, 1040, 960, 930, 840, 730. 
TABLE 8 
__________________________________________________________________________ 
Average 
Weight- 
Ref. Amount 
Amount 
Amount Composition 
Polymeri- 
average 
Example 
of PET 
of CL 
of VL 
Yield, g 
a/b zation 
Molecular 
No. g (mmol) 
g (mmol) 
g (mmol) 
(% yield) 
mol % Degree 
Weight 
__________________________________________________________________________ 
30 0.086 
5.47 1.20 5.29 80/20 22.4 4.68 .times. 10.sup.4 
(0.599) 
(47.9) 
(12.0) 
(78.3) 
31 1.19 80.0 3.51 75.9 95/5 19.9 3.38 .times. 10.sup.4 
(8.74) 
(701) 
(35.0) 
(89.6) 
__________________________________________________________________________ 
##STR22## 
1 g of the trifunctional or tetrafunctional polyester macromonomer obtained 
in each of Referential Examples 1 to 31, 0.01 g of 
N,N-dimethyl-p-toluidine and 0.01 of camphorquinone were dissolved in 1 g 
of xylene. A spacer made from polytetrafluoroethylene having a thickness 
of 0.1 mm was inserted between two glass plates each having a size of 10 
cm.times.10 cm, and the above-prepared xylene solution was injected into 
the space between the glass plates. The glass plates were uniformly 
irradiated with visible light at an intensity of about 0.5 mW/cm.sup.2 for 
10 minutes thereby polymerizing the macromonomer to obtain a colorless 
transparent gel membrane having a thickness of from 60 to 90 .mu.m. The 
membrane was immersed in acetone for about 8 hours to remove the initiator 
and sensitizer contained wherein and then thoroughly dried under reduced 
pressure. 
Test Example 1 (Measurement of Mechanical Properties) 
A part of the polyester gel membrane obtained in each of Referential 
Examples 32 to 62 was subjected to a tensile test, and the tensile 
modulus, the tensile strength and the maximum elongation percentage were 
calculated from the stress-strain diagram obtained by the tensile test. 
The results obtained are shown in Table 9. 
As is noted from the results shown in Table 9, gel membranes having various 
modulus, strength and elongation percentage can be prepared from the 
polyfunctional macromonomers having different constituting components of 
the polymer chain and average polymerization degrees. 
TABLE 9 
______________________________________ 
Maximum 
Ref. Ref. Example 
Tensile Tensile 
Elongation 
Example No. of starting 
Modulus Strength 
Percentage 
No. Macromonomer 
MPa MPa % 
______________________________________ 
32 1 3.72 0.904 62.3 
33 2 109 8.89 195 
34 3 322 9.38 239 
35 4 145 7.77 89.0 
36 5 16.3 2.70 25.8 
37 6 16.0 1.76 45.4 
38 7 104 9.39 196 
39 8 144 9.04 45.4 
41 10 1050 21.9 71.9 
42 11 55.9 6.43 380 
43 12 1310 32.2 13.6 
44 13 1610 31.6 7.37 
45 14 831 38.1 10.3 
46 15 11.2 6.57 182 
47 16 4.64 1.21 56.4 
48 17 16.9 8.96 196 
49 18 0.732 0.473 109 
50 19 2.27 0.683 102 
51 20 4.53 1.89 52.7 
52 21 45.6 4.19 158 
53 22 109 14.7 883 
54 23 2.27 1.04 90.2 
55 24 3.02 0.90 57.5 
______________________________________ 
Test Example 2 (Thermal Properties) 
A part of the polyester gel membrane obtained in Each of Referential 
Examples 32 to 62 was tested for a transition temperature of gel using a 
differential scanning calorimeter, and the results obtained are shown in 
Table 10 below. The transition temperatures in the Table represent maximum 
points of heat absorption peaks. 
As is noted from the results shown in Table 10, each of the gels showed a 
phase transition temperature of high transition enthalpy, and the 
transition temperature was found to be different depending upon the 
difference in the constituting components of the polyester chain and the 
average polymerization degree. 
TABLE 10 
______________________________________ 
Ref. 
Transition 
Ref. Example Transition 
Example No. of starting 
Temperature 
Enthalpy 
No. Macromonomer .degree.C. mJ/mg 
______________________________________ 
37 6 41.2 15.0 
38 7 44.0 30.0 
39 8 50.3 52.7 
40 9 55.0 59.2 
53 22 45.5 31.3 
56 25 49.0 49.4 
57 26 46.3 32.5 
58 27 38.7 27.1 
59 28 46.2 49.0 
60 29 51.4 58.7 
61 30 35.8 34.3 
62 31 46.6 44.1 
______________________________________ 
EXAMPLES 1 TO 3 
The gel membrane obtained in each of Referential Examples 38, 39 and 53 was 
put between two chambers of a two-chamber diffusion cell (effective 
cross-sectional area: 0.95 cm.sup.2), and 2 ml of a phosphate buffer 
adjusted to pH 7.4 containing a saturated amount (about 7 mg, about 0.3 wt 
%) of an anti-inflammatory agent, indomethacin, was placed into the donor 
section, and 2 ml of a phosphate buffer adjusted to pH 7.4 was placed into 
the receptor section. The whole of the cell was then dipped into a 
thermostat tank adjusted to a predetermined temperature. The temperature 
of the tank was maintained at a constant temperature in the range of from 
20 .degree. C. to 55.degree. C. in a step of 5 .degree. C. The receptor 
solution was sampled from the receptor section in every 20 minutes, and 
indomethacin permeated through the gel membrane was quantitatively 
determined by high performance liquid chromatography. The change in the 
concentration of permeated indomethacin with the lapse of time was 
determined from the slope of permeation curve in a stationary state 
obtained by plotting the accumulated amount of indomethacin permeated into 
the receptor section at the sampling time with respect of time passed. 
Then, from the change in the concentration of indomethacin with the time 
at each of the test temperatures, a permeation coefficient P of 
indomethacin permeated through the membrane was calculated by the 
following equation (1): 
EQU P=(V dC/dt)/(A Cv) (1) 
wherein: 
V: Volume of the receptor section 
dC/dt: Change in concentration of indomethacin in the receptor section with 
the time passed 
A: Area of membrane 
Cv: Concentration of indomethacin in receptor section 
The permeation coefficient P of indomethacin permeated through each of the 
gel membranes at each of the test temperatures is shown in Table 11 below. 
As shown in Table 11, it was found that the value of P markedly increased 
at a specific temperature in each of the gel membranes. 
TABLE 11 
______________________________________ 
Permeation Coefficient P (cm/sec) 
Gel Gel Gel 
Temperature at 
Membrane Membrane Membrane 
Measurement 
of Ref. of Ref. of Ref. 
(.degree.C.) 
Example 38 Example 39 Example 53 
______________________________________ 
20 1.01 .times. 10.sup.-6 
1.32 .times. 10.sup.-7 
1.30 .times. 10.sup.-7 
25 1.85 .times. 10.sup.-6 
1.87 .times. 10.sup.-7 
1.82 .times. 10.sup.-7 
30 3.85 .times. 10.sup.-6 
4.89 .times. 10.sup.-7 
2.12 .times. 10.sup.-7 
35 5.66 .times. 10.sup.-6 
8.53 .times. 10.sup.-7 
1.71 .times. 10.sup.-6 
40 1.52 .times. 10.sup.-5 
3.32 .times. 10.sup.-6 
5.82 .times. 10.sup.-6 
45 3.08 .times. 10.sup.-5 
2.94 .times. 10.sup.-5 
2.20 .times. 10.sup.-5 
50 4.00 .times. 10.sup.-5 
4.08 .times. 10.sup.-5 
3.31 .times. 10.sup.-5 
55 6.04 .times. 10.sup.-5 
5.57 .times. 10.sup.-5 
6.50 .times. 10.sup.-5 
______________________________________ 
EXAMPLES 4 TO 6 
The gel membrane obtained in each of Referential Examples 38, 39 and 53 was 
put between two chambers of a two-chamber diffusion cell (effective 
cross-sectional area: 0.95 cm.sup.2), and 2 ml of a phosphate buffer 
adjusted to pH 7.4 containing a saturated amount (about 7 mg, about 0.3 wt 
%) of an anti-inflammatory agent indomethacin was placed into the donor 
section, and 2 ml of a phosphate buffer adjusted to pH 7.4 was placed into 
the receptor section. The whole of the cell was then dipped into a 
thermostat tank adjusted to a predetermined temperature. The temperature 
of the tank was changed in two and half cycles at two different 
temperatures of 20.degree. C.-40.degree. C.-20.degree. C.-40.degree. 
C.-20.degree. C. or 30.degree. C.-50.degree. C.-30.degree. C.-50.degree. 
C.-30.degree. C. at an interval of 2 hours. A portion of the solution was 
taken out from the receptor section in every 20 minutes, and indomethacin 
permeated through the gel membrane was quantitatively determined by high 
performance liquid chromatography. The accumulated amount of indomethacin 
permeated into the receptor section at the sampling time was plotted with 
respect to time passed to obtain FIGS. 1 to 3 which correspond to the 
results obtained in Referential Examples 4 to 6, respectively. 
As is noted from the graphs, in each of the gel membranes, the permeation 
rate of indomethacin markedly differ at temperatures below or above the 
transition temperature thereof, i.e., a lower rate in a lower temperature 
side and a higher rate in a higher temperature side, and it was confirmed 
that the indomethacin releasing rate can be controlled depending upon the 
change in temperature. Accordingly, these gels were found to have a 
function as a material for controlling the drug release responsive to 
changes in temperature. 
EXAMPLES 7 TO 13 
##STR23## 
The trifunctional or tetrafunctional polyester macromonomer obtained in 
each of Referential Examples 8, 22, or 29, and the polyethylene glycol 
derivative represented by the above formula (21) were mixed in amounts 
described in Table 12. Then the mixture was dissolved in 1 g of xylene, 
together with 0.01 g of N,N-dimethyl-p-toluidine and 0.01 of 
camphorquinone. A spacer made from polytetrafluoroethylene having a 
thickness of 0.1 mm was inserted between two glass plates each having a 
size of 10 cm.times.10 cm, and the above-prepared xylene solution was 
injected into the space between the glass plates. The glass plates were 
uniformly irradiated with visible light at an intensity of about 0.5 
mW/cm.sup.2 for 10 minutes thereby polymerizing the macromonomer and the 
polyethylene glycol derivative to obtain a colorless transparent gel 
membrane having a thickness of about 150 .mu.m. The membrane was immersed 
in acetone for about 8 hours to remove the initiator and sensitizer 
contained wherein and then thoroughly dried under reduced pressure. 
The polyester gel membrane obtained in each of Examples 7 to 13 was tested 
for a transition temperature of gel using a differential scanning 
calorimeter, and the results obtained are shown in Table 12 below. The 
transition temperatures in the Table represent maximum points of heat 
absorption peaks. 
As is noted from the results shown in Table 12, each of the gels showed a 
phase transition temperature of high transition enthalpy, and the 
transition temperature was found to be different depending upon the 
difference in the constituting components of the polyester chain and the 
average polymerization degree. 
TABLE 12 
__________________________________________________________________________ 
Starting 
Macromonomer PEG deriv. 
Ref. Average Transition 
Transition 
Example 
Example 
Weight 
Degree of 
Weight 
Temperature 
Enthalpy 
No. No. (g) (n) (g) (.degree.C.) 
(mJ/mg) 
__________________________________________________________________________ 
7 8, 0.80 
23 0.20 
48.0 39.6 
8 8, 0.90 
23 0.10 
48.6 51.7 
9 8, 0.95 
23 0.05 
49.0 55.6 
10 8, 0.95 
9 0.05 
50.3 54.7 
11 22, 0.90 
23 0.10 
49.8 44.0 
12 22, 0.95 
23 0.05 
50.0 46.0 
13 29, 0.95 
23 0.05 
51.6 63.9 
__________________________________________________________________________ 
EXAMPLES 14 TO 15 
##STR24## 
1 g of the trifunctional or tetrafunctional polyester macromonomer obtained 
in Referential Example 8 and the polyethylene glycol derivative 
represented by the formula (22) were mixed in amounts described in Table 
12. Then the mixture was dissolved in 1 g of xylene, together with 0.01 g 
of N,N-dimethyl-p-toluidine and 0.01 of camphorquinone. A spacer made from 
polytetrafluoroethylene having a thickness of 0.1 mm was inserted between 
two glass plates each having a size of 10 cm.times.10 cm, and the 
above-prepared xylene solution was injected into the space between the 
glass plates. The glass plates were uniformly irradiated with visible 
light at an intensity of about 0.5 mW/cm.sup.2 for 10 minutes thereby 
polymerizing the macromonomer and the polyethylene glycol derivative to 
obtain a colorless transparent gel membrane having a thickness of about 
150 .mu.m. The membrane was immersed in acetone for about 8 hours to 
remove the initiator and sensitizer contained wherein and then thoroughly 
dried under reduced pressure. 
The resulting gel membranes were tested for a transition temperature of gel 
using a differential scanning calorimeter, and the results obtained are 
shown in Table 13 below. The transition temperatures in the Table 
represent maximum points of heat absorption peaks. 
TABLE 13 
__________________________________________________________________________ 
Starting 
Macromonomer PEG deriv. 
Ref. Ref. Average Transition 
Transition 
Example 
Example 
Weight 
Degree of 
Weight 
Temperature 
Enthalpy 
No. No. (g) Polym. (n) 
(g) (.degree.C.) 
(mJ/mg) 
__________________________________________________________________________ 
14 8, 0.95 
14 0.05 
49.8 41.3 
15 8, 0.95 
23 0.05 
50.5 55.6 
__________________________________________________________________________ 
EXAMPLE 16 
The gel membrane obtained in Example 7 was put between two chambers of a 
two-chamber diffusion cell (effective cross-sectional area: 0.95 
cm.sup.2), and 2 ml of a phosphate buffer adjusted to pH 7.4 containing a 
saturated amount (about 7 mg, about 0.3 wt %) of an anti-inflammatory 
agent indomethacin was placed into the donor section, and 2 ml of a 
phosphate buffer adjusted to pH 7.4 was placed into the receptor section. 
The whole of the cell was then dipped into a thermostat tank adjusted to a 
predetermined temperature. The temperature of the tank was changed in two 
and half cycles at two different temperatures of 20.degree. C.-40.degree. 
C.-20.degree. C. -40.degree. C.-20.degree. C. at an interval of 2 hours. A 
portion of the solution was taken out from the receptor section in every 
20 minutes, and indomethacin permeated through the gel membrane was 
quantitatively determined by high performance liquid chromatography. The 
accumulated amount of indomethacin permeated into the receptor section at 
the sampling time was plotted with respect to time passed to obtain FIG. 
4. 
As is noted from the graph, the gel membrane shows enhanced permeation rate 
of indomethacin, and the permeation rate markedly differ at temperatures 
below or above the transition temperature thereof, i.e., a lower rate in a 
lower temperature side and a higher rate in a higher temperature side. 
Thus, it was confirmed that the indomethacin releasing rate can be 
controlled depending upon the change in temperature. Accordingly, these 
gels were found to have a function as a material for controlling the drug 
release responsive to changes in temperature. 
EXAMPLE 17 to 25 
The gel membrane obtained in each of Referential Example 39 and Examples 8 
to 15 was put between two chambers of a two-chamber diffusion cell 
(effective cross-sectional area: 0.95 cm.sup.2), and 2 ml of a phosphate 
buffer adjusted to pH 7.4 containing 10 mg (0.5 wt %) of antipyrine was 
placed into the donor section, and 2 ml of a phosphate buffer adjusted to 
pH 7.4 was placed into the receptor section. The whole of the cell was 
then dipped into a thermostat tank adjusted to a predetermined 
temperature. The temperature of the tank was changed in two and half 
cycles at two different temperatures of 20.degree. C.-40.degree. 
C.-20.degree. C.-40.degree. C.-20.degree. C. at an interval of 2 hours. A 
portion of the solution was taken out from the receptor section in every 
20 minutes, and antipyrine permeated through the gel membrane was 
quantitatively determined by high performance liquid chromatography. The 
accumulated amount of antipyrine permeated into the receptor section at 
the sampling time was plotted with respect to time passed to obtain FIGS. 
5 to 13 which correspond to the results obtained in Referential Examples 
17 to 25, respectively. 
As is noted from the graph, the gel membrane shows enhanced permeation rate 
of antipyrine, and the permeation rate markedly differ at temperatures 
below or above the transition temperature thereof, i.e., a lower rate in a 
lower temperature side and a higher rate in a higher temperature side. 
Thus, it was confirmed that the antipyrine releasing rate can be 
controlled depending upon the change in temperature. Accordingly, these 
gels were found to have a function as a material for controlling the drug 
release responsive to changes in temperature. 
While the invention has been described in detail and with reference to 
specific embodiments thereof, it will be apparent to one skilled in the 
art that various changes and modifications can be made therein without 
departing from the spirit and scope thereof.