JP3487703B2 - Bioabsorbable polyester and method for producing the same - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a bioabsorbable polyester and a method for producing the same. Specifically, it relates to a bioabsorbable polyester obtained by ring-opening polymerization of a cyclic ester compound such as glycolide or lactide using a specific aromatic compound as an initiator, and a method for producing the same. More specifically, the present invention relates to the above bioabsorbable polyester that can be used as a medical device such as a surgical suture, a base material for a sustained release drug, a bone graft plate for fracture, and a method for producing the same.

[0002]

2. Description of the Related Art Polyglycolic acid, polylactic acid, polycaprylactone, and copolymers of these with other hydroxycarboxylic acids are known as bioabsorbable polyesters. For example, in the case of a glycolic acid-based polymer such as polyglycolic acid or a copolymer of glycolic acid and another hydroxycarboxylic acid, a polymer having a high molecular weight has high mechanical strength but poor solubility in a solvent and a melting point. 180-240
Since it has a high moldability of as high as ℃, it is used as a surgical material such as sutures and meshes after being processed into fibrous form.

Further, in the case of a lactic acid-based polymer such as polylactic acid or a copolymer of lactic acid and another hydroxycarboxylic acid, it has excellent processability and solubility in a solvent, and a high molecular weight one has a rod shape or a plate shape. As a processed bone graft plate,
It is also processed into needles and films, and is used as various molding materials in vivo. Those having a relatively low molecular weight are mainly used as base materials for sustained-release drugs.

These bioabsorbable polyesters are used in vivo for about 3 months in the case of PGA and 6 months to 1 in the case of PLA.
In the case of PLGA, PLGA is hydrolyzed in several weeks, and various decomposition periods are required depending on its type and purpose of use.

In response to such a demand, Japanese Patent Laid-Open No. 63-1
No. 7929, in the presence of stannous octoate, 0.11 to 0.22 mol% of a linear aliphatic monohydric alcohol having 10 to 18 carbon atoms relative to glycolide is used as an initiator. , 220-250 [deg.] C., a method for producing polyglycolic acid having an intrinsic viscosity of 0.85-1.1 is proposed.

On the other hand, regarding the method for producing a lactic acid-based polymer,
Japanese Patent Application Laid-Open No. 62-64824 discloses a lactic acid unit of 25 to 1
00 mol% and 0-75 mol% glycolic acid units, 0.2 wt% tin octoate was used as the catalyst, dl
-A lactic acid-glycolic acid copolymer having an intrinsic viscosity of 4 or less, which is polymerized in the presence of lactic acid at a temperature of 160 ° C, and a method for producing the same are described.

As described above, regarding the method for producing a bioabsorbable polyester, a method of ring-opening polymerization of glycolide or lactide, which is a cyclic dimer of glycolic acid or lactic acid, with an appropriate catalyst is disclosed. As the agent, a method using a linear aliphatic alcohol such as lauryl alcohol and an oxyacid such as dl-lactic acid is known.

However, in any of the above-mentioned production methods, the hydrolysis rate is controlled by adjusting the addition amount of the initiator used in the polymerization. That is, the conventionally used method is to control the degradability by adjusting the molecular weight. Specifically, it is a method of decreasing the amount of the initiator to obtain a high molecular weight polymer and increasing the amount of the initiator to obtain a low molecular weight polymer. In this case, there arises the contradictory problem that a polymer having a high molecular weight is excellent in physical strength but is deteriorated in hydrolyzability, and a polymer having a low molecular weight is quick in hydrolysis but inferior in physical strength. Therefore, there has been a demand for a bioabsorbable polyester having a suppressed hydrolyzability despite its low molecular weight, and a method for producing the same.

[0009]

The object of the present invention is to provide a bioabsorbable compound obtained by ring-opening a cyclic ester compound using a new initiator other than the above, which has a phenyl group bonded to the molecular end by an ester bond. A polyester and a method for producing the same are provided.

[0010]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies on the above problems, and as a result, at the time of ring-opening polymerization of cyclic ester compounds such as glycolide and lactide, at least one of a hydroxyl group and a carboxyl group is selected. It was found that the above problems can be solved by using an aromatic compound having a specific structure as an initiator, and the present invention has been completed.

That is, the present invention is a bioabsorbable polyester obtained by ring-opening polymerization of a cyclic ester compound, which is represented by the general formula (1)

[0012]

[Chemical 5] (In the formula, R ₁ and R ₂ are alkyl groups having 1 to 3 carbon atoms,
_{H, -OH, -OCH 3, -OCOCH} 3, -COOH,
_{-COOCH 3, -COOC 2 H 5,} -NH 2, -NHCH
_3, -N (CH _{3) 2,} a -NHCOCH _3, compounds also represented by the different may be) the same to each other, and the general formula (2) [Formula 6]

[0013]

[Chemical 6] (In the formula, R ₃ and R ₄ are alkyl groups having 1 to 3 carbon atoms,
_{H, -OH, -OCH 3, -OCOCH} 3, -COOH,
_{-COOCH 3, -COOC 2 H 5,} -NH 2, -NHCH
_{3, -N (CH 3) 2} , a -NHCOCH _3, at least one aromatic compound as an initiator selected from the compounds represented by may also be different) identical to one another, relative to the cyclic ester compound A bioabsorbable polyester obtained by using 0.002 to 1 mol% and a method for producing the same.

The bioabsorbable polyester of the present invention is obtained by ring-opening polymerization of a cyclic ester compound using an aromatic compound having a specific structure having at least one of a hydroxyl group and a carboxyl group as an initiator. The point is that it is a thing.

It is generally said that the hydrolysis of bioabsorbable polyesters begins at the end of the polymer chain. Thus, the bioabsorbable polyester of the present invention, when the ring-opening polymerization of the cyclic ester compound, is obtained by using an aromatic compound having a specific structure as an initiator,
A phenyl group is bonded to the end of the polymer chain by an ester bond. Therefore, for example, the molecular weight is 50,000 to 2
In the case of a polymer having a molecular weight of about 0,000, since the ratio of the molecular ends in the whole polymer molecule is high, it has a unique property that the hydrolyzability is suppressed (slow) as compared with the conventional polyester. Therefore, when the bioabsorbable polyester of the present invention is used, for example, as a base material for a sustained-release drug, the drug efficacy period is maintained for a long period of time, and a sustained-release drug for a disease or a disease with a long healing period is used. It is particularly useful as a substrate. Further, the above-mentioned initiator used in the present invention is a substance which is not harmful to the human body, and is also useful as an initiator for ring-opening polymerization of a cyclic ester compound from this point of view.

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below. As the cyclic ester compound used for producing the bioabsorbable polyester of the present invention, glycolide,
Lactide, β-propiolactone, β-butyrolactone, δ-valerolactone, ε-caprolactone, 3-methyl-1,4-dioxa-2,5-dione, p-dioxanone, morpholinedione, morpholine and the like. You can These may be used alone, or
You may mix and use 2 or more types. Among the above cyclic ester compounds, glycolide and lactide are preferably used. When these copolymers are produced using a mixture of cyclic ester compounds, the mixing ratio of each is
It can be changed depending on the use of the obtained bioabsorbable polyester.

For example, in the case of a glycolic acid polymer such as polyglycolic acid (hereinafter referred to as PGA), 100,000 to 2
Those having a high molecular weight of about 0,000 are processed into fibers and used as surgical materials such as sutures and meshes. In this case, the glycolic acid unit is usually 80 to
It is adjusted to be about 100 mol% and the lactic acid unit is about 0 to 20 mol%. Lactic acid-based polymers such as polylactic acid (hereinafter,
In the case of PLA), a polymer having a high molecular weight of about 200,000 to 300,000 is processed into a rod shape or a plate shape to be used as a bone-contacting plate, and is also processed into a needle shape or a film shape to be used as various sex shaping materials in vivo. Used. In this case, the lactic acid unit is usually adjusted to be approximately 100 mol% in the polyester. In addition, lactic acid-glycolic acid, etc. (hereinafter PLGA
In the case of), it is mainly used as a base material for a sustained-release drug. In this case, the molecular weight is usually about 50,000 to 200,000,
The number of glycolic acid units in the polyester exceeds 0 to 80
It is adjusted so that the mol% and the lactic acid unit are less than 20 to 100 mol%.

A catalyst is preferably used when producing the bioabsorbable polyester of the present invention. Examples of the catalyst include tin chloride, tin oxide, tin fluoride, tetraphenyl tin, stannous octoate, tin acetate, tin stearate and tin salts thereof, as well as lead oxide, zinc oxide and trifluoride. Examples thereof include boron, antimony trifluoride, lead stearate, triethylamine, tributylamine, tributylphosphine and the like. Among these, it is preferable to use stannous octoate, which is approved by the US FDA, as a non-toxic stabilizer. The amount of the catalyst used is appropriately determined depending on the type and the polymerization temperature, but is preferably about 0.
001 to 0.5% by weight.

In the present invention, a ring is formed in the presence of the above catalyst.
The initiator used in the ring-opening polymerization of the ester compound is
Aromatization represented by the above general formulas (1) and (2)
It is a combination. These may be used alone or
Also, two or more kinds may be mixed and used. The above general formula
R of the substituent in (1) and the general formula (2)₁, R₂, R
₃And R_FourIs a hydroxyl group or carboxyl group.
Attached to any carbon in the luso, meta or para position
Good. Substituent R₁, R₂, R₃And R_FourAs for the next
One of them is. For example, 1) H or 1 to 1 carbon atoms
3 alkyl group, 2) OH group, or a derivative thereof
(-OCH₃), (-OCOCH₃), 3) COOH
A group or a derivative thereof (-COOCH₃),
(-COOC₂H _Five), 4) NH₂Group or its derivation
Body (-NHCH₃), (-N (CH)₂, -NHC
OCH₃) Etc. are illustrated.

Specific examples include o, m, p-cresol, o, and the aromatic compound represented by the general formula (1).
m, p-ethylphenol, catechol, resorcinol, hydroquinone, o, m, p-hydroxybenzoic acid, o, m, methyl p-hydroxybenzoate, o, m,
Examples thereof include ethyl p-hydroxybenzoate, catechol monomethyl ether, resorcinol monomethyl ether, hydroquinone monomethyl ether, catechol monoacetate, resorcinol monoacetate, hydroquinone monoacetate, and aminophenol, nitrophenol, cyanophenol, thiophenol and the like.

As the aromatic compound represented by the general formula (2), 2,3,4-methylbenzoic acid, 2,3,4-
Examples thereof include ethylbenzoic acid, phthalic acid, isophthalic acid, terephthalic acid, acetylsalicylic acid, aminobenzoic acid and nitrobenzoic acid. Moreover, as a trifunctional group, aminosalicylic acid, diaminophenol, 2, 4
-Hydroxybenzoic acid, 4-amino-2-sulfobenzoic acid and the like can be mentioned.

Of the above-mentioned aromatic compounds, those which have low toxicity to the living body and which are used for designing medical polymer materials such as bioabsorbable polyester are preferable. Considering this point, acetylsalicylic acid, acetaminophen, methyl salicylate, ethyl salicylate and the like are particularly preferable.

The amount of these initiators used affects the molecular weight of the resulting bioabsorbable polyester. If the amount used is large, the rate of ring-opening polymerization will increase and the molecular weight will decrease.
When the amount used is small, the rate of ring-opening polymerization becomes slow and the molecular weight becomes high. The preferable molecular weight varies depending on the intended use of the bioabsorbable polyester, and can be appropriately determined depending on the use.

For example, when it is used as a suture, an osteoclastic plate, a base material for a sustained-release drug, etc., the initiator concentration is usually 0.002 to 1 mol%, preferably 0.1% to the cyclic ester compound. It is used in the range of 01 to 0.1 mol%. If it is less than 0.002 mol%, not only the polymerization reaction rate is slow, but also the molecular weight becomes too high and the ratio of the polymer chain ends in the entire polymer becomes low, so that a phenyl group is introduced into the polymer chain ends via an ester bond. It is hard to see the effect. If it exceeds 1 mol%, the effect of introducing a phenyl group through an ester bond at the polymer chain end will appear, but the strength of the bioabsorbable polyester will tend to decrease significantly, and the original characteristics of the bioabsorbable polymer It is difficult to control the degradability. From this point of view, it is preferably used within the above range.

The polymerization reaction can be carried out by solution polymerization using a solvent, for example, an organic solvent such as chloroform or dichloromethane, but it is usually preferable to carry out bulk polymerization in a molten state. In the case of melt polymerization, the polymerization temperature may be equal to or higher than the melting point of raw material monomers such as glycolide and lactide. Specifically, 140 to 24
A temperature range of about 0 ° C. is included. In the case of solution polymerization using a solvent such as chloroform / dichloromethane,
The reaction can be carried out at a temperature below these melting points. Specifically, a temperature range of 50 ° C. to a temperature lower than the boiling point of the solvent used can be mentioned.

The present invention obtained by the above manufacturing method
Ming bioabsorbable polyester is a well-known initiator, for example,
For example, straight-chain aliphatic alcohol such as lauryl alcohol, d
Bioabsorbable poly (ethylene glycol) with oxy acid such as l-lactic acid as an initiator
A stell is an ester bond at the end of the polymer chain.
Different molecular structure in that more phenyl groups are bonded
It is a thing. Differences in polymer structure are hydrolyzable, solution
Since it is related to viscosity, solubility in a solvent, etc.,
Such as having a phenyl group at the terminal via an ester bond
Body absorbable polyesters exhibit unique hydrolyzability. Book
The bioabsorbable polymer of the invention has an ester bond at the end.
That the phenyl group is bound to¹ H-NMR (nucleus
Peak in magnetic resonance spectrum, IR (infrared absorption spectrum)
Peak or gel permeation chromatography
It can be easily confirmed by matography.

[0027]

EXAMPLES The present invention will be described in more detail below with reference to examples. The physical properties in the examples were measured by the following methods.

(1) Weight average molecular weight and molecular weight distribution The polymer is dissolved in chloroform or hexafluoroisopropanol (hereinafter abbreviated as HFIP) to give a solution having a concentration of 0.5% (polymer: weight, solvent: volume). Gel permeation chromatography (hereinafter referred to as G
Weight average molecular weight (Mw)
And the number average molecular weight (Mn) are obtained. When chloroform is used as a solvent, polystyrene conversion is used, and HFIP
When is used, it is calculated in terms of polymethylmethacrylate. Further, the molecular weight distribution is calculated from the ratio of both (Mw / Mn).

(2) Retention rate of molecular weight (%) in hydrolyzability test A sample was ground into a powder with a small grinder, and 1 g of the sample was placed in a test tube with a stopper, and a phosphate buffer solution (pH 7.3). 20
Add ml. The test tube was fixed in a constant temperature bath at 37 ° C, and after 2 weeks, the sample was taken out, dried under reduced pressure, and then Mw by GPC.
To measure. The molecular weight retention rate (%) is calculated by the following formula. (Mw of the sample after a certain period of time) × 100 /
(Mw of initial sample)

(3) A nuclear magnetic resonance spectrum sample was dissolved in deuterated chloroform or a mixed solution of HFIP / deuterated chloroform (volume ratio: 1/10),
After preparing a 10% (polymer: weight, solvent: volume) sample solution, the sample solution was put into a test tube having a diameter of 5 mm, and 100 MHz NMR was used.
It measures using a measuring device and confirms the peak based on a phenyl group in 7.8 ppm.

(4) Infrared absorption spectrum It is measured by the KBr tablet method, and a peak based on a phenyl group at 1560 cm ^-1 is confirmed.

Example 1 5.0 g of glycolide (hereinafter referred to as GLD) and DL
-Lactide (hereinafter, referred to as DL-LTD) 5.0 g was put into an ampoule tube for polymerization, and stannous octoate as a catalyst was 0.01 wt% with respect to GLD and DL-LTD.
And acetylsalicylic acid as an initiator to GLD and DL
-Add 0.35 mol% with respect to LTD, and at room temperature for 1 m
After drying under reduced pressure at mHg for 1 hour, the ampoule tube was sealed and polymerized at a reaction temperature of 160 ° C. for 6 hours to obtain GLD-LTD.
A copolymer was obtained. The nuclear magnetic resonance spectrum of the obtained copolymer was measured by the above-mentioned method.
A peak based on a phenyl group was confirmed in pm. Also,
As a result of measuring the infrared absorption spectrum by the above method, 1
A peak based on a phenyl group was confirmed at 560 cm ^-1 . Further, the molecular weight, the molecular weight distribution and the molecular weight retention rate in the hydrolysis test were measured by the above-mentioned methods. The obtained results are shown in [Table 1].

Examples 2-8, Comparative Examples 1-7 GLD-LTD was carried out in the same manner as in Example 1 except that the type and amount of the initiator used were changed as shown in [Table 1].
A copolymer was obtained. The nuclear magnetic resonance spectrum and the infrared absorption spectrum of the obtained copolymer were measured by the above methods, and the result was 7.8 ppm (NMR), or 156
A peak based on a phenyl group was confirmed at 0 cm ^-1 (IR). Further, the molecular weight, the molecular weight distribution, and the molecular weight retention rate in the hydrolysis test were measured by the above methods.
The obtained results are shown in [Table 1].

[0034]

[Table 1]

[0035]

The bioabsorbable polyester of the present invention is characterized by being obtained by ring-opening polymerization of a cyclic ester compound in the presence of an aromatic compound having at least one of a hydroxyl group and a carboxylic acid group. is there. Therefore, it has a phenyl group at the end of the polymer chain through an ester bond. Therefore, even if the molecular weight is low, the hydrolyzability becomes slow. For example, when it is used as a base material for sustained-release drugs, the drug efficacy will be maintained for a long period of time,
It is particularly useful as a base material for a sustained-release drug used for diseases and diseases having a long healing period. This effect becomes more remarkable when the molecular weight is about 50,000 to 200,000. In addition, those having a high molecular weight of more than 100,000 are useful in the medical field such as surgical sutures and bone graft plates for fractures.

─────────────────────────────────────────────────── ─── Continuation of the front page (58) Fields surveyed (Int.Cl. ⁷ , DB name) C08G 63/00-63/91

Claims (8)

(57) [Claims] 1. A bioabsorbable polyester obtained by ring-opening polymerization of a cyclic ester compound, which is represented by the general formula (1):
[Chemical formula 1] [Chemical formula 1] (In the formula, R ₁ and R ₂ are alkyl groups having 1 to 3 carbon atoms,
_{H, -OH, -OCH 3, -OCOCH} 3, -COOH,
_{-COOCH 3, -COOC 2 H 5,} -NH 2, -NHCH
_3, -N (CH _{3) 2,} a -NHCOCH _3, compounds also represented by the different may be) the same to each other, and the general formula (2) [Formula 2] [Formula 2] (In the formula, R ₃ and R ₄ are alkyl groups having 1 to 3 carbon atoms,
_{H, -OH, -OCH 3, -OCOCH} 3, -COOH,
_{-COOCH 3, -COOC 2 H 5,} -NH 2, -NHCH
_{3, -N (CH 3) 2} , a -NHCOCH _3, at least one aromatic compound as an initiator selected from the compounds represented by may also be different) identical to one another, relative to the cyclic ester compound Bioabsorbable polyester obtained by using 0.002 to 1 mol%. 2. The cyclic ester compound is at least one compound selected from glycolide and lactide,
The bioabsorbable polyester according to claim 1, wherein the bioabsorbable polyester has a molecular weight of 50,000 to 300,000. 3. R ₁ or R ₃ in the general formula (1) and the general formula (2) are both —H, and R ₂ and R ₄ are an alkyl group having 1 to 3 carbon atoms, —COOH, — COOCH ₃ ,
-COOC ₂ H _5, -NHCOCH _3, and, -OCOC
The bioabsorbable polyester according to claim 1, which is a monovalent group selected from H ₃ . 4. R ₁ or R ₃ in the general formula (1) and the general formula (2) are both —H, and R ₂ and R ₄ are —NH.
The bioabsorbable polyester according to claim 1, which is a monovalent group selected from COCH ₃ and —OCOCH ₃ . 5. A method for producing a bioabsorbable polyester by ring-opening polymerization of a cyclic ester compound, which comprises a compound represented by the general formula (1):
[Chemical Formula 3] [Chemical Formula 3] (In the formula, R ₁ and R ₂ are alkyl groups having 1 to 3 carbon atoms,
_{H, -OH, -OCH 3, -OCOCH} 3, -COOH,
_{-COOCH 3, -COOC 2 H 5,} -NH 2, -NHCH
_3, -N (CH _{3) 2,} a -NHCOCH _3, a compound represented by may also be different) identical to one another, and the general formula (2) [Formula 4] [Chemical Formula 4] (In the formula, R ₃ and R ₄ are alkyl groups having 1 to 3 carbon atoms,
_{H, -OH, -OCH 3, -OCOCH} 3, -COOH,
_{-COOCH 3, -COOC 2 H 5,} -NH 2, -NHCH
_{3, -N (CH 3) 2} , a -NHCOCH _3, at least one aromatic compound as an initiator selected from the compounds represented by may also be different) identical to one another, relative to the cyclic ester compound A method for producing a bioabsorbable polyester, which comprises using 0.002 to 1 mol%. 6. The cyclic ester compound is at least one compound selected from glycolide and lactide,
The method for producing the bioabsorbable polyester according to claim 5, wherein the bioabsorbable polyester has a molecular weight of 50,000 to 300,000. 7. R ₁ or R ₃ in the general formula (1) and the general formula (2) are both —H, and R ₂ and R ₄ are an alkyl group having 1 to 3 carbon atoms, —COOH, —COOCH. ₃ ,-
COOC ₂ H ₅ , -NHCOCH ₃ , and -OCOCH ₃
7. A monovalent group selected from the group consisting of:
A method for producing the bioabsorbable polyester described above. 8. R ₁ or R ₃ in the general formula (1) and the general formula (2) are both —H, and R ₂ and R ₄ are —NH.
COCH _3, and The method according to claim 6, wherein the bioabsorbable polyester, which is a monovalent group selected from -OCOCH _3.