JP2704330B2 - Biodegradable polymer - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a biodegradable polymer,
Particularly, the present invention relates to a polymer which imparts excellent sustained-release properties when a drug or the like is complexed with the polymer.

[0002]

2. Description of the Related Art In recent years, polymers such as lactic acid and glycolic acid, that is, polylactide and polyglycolide have been applied to medical materials such as sutures and artificial organs as biodegradable polymers. On the other hand, various studies have been made as a base for a drug delivery system (DDS) for controlling the administration of a drug to a living body.

[0003] Desirable characteristics of such a DDS base include, when the drug-containing complex is implanted in a living body,
Release a certain amount of drug into the living body at a predetermined time,
Degradation is rapid after drug release. It is also desired that the DDS base does not contain impurities such as a polymerization catalyst and has good biocompatibility.

Conventionally known bases include lactic acid,
There are homopolymers and copolymers such as glycolic acid, and among these bases, amorphous polymers are frequently used. This is because when an amorphous polymer is used as a DDS base, the drug dispersibility is superior to that of the crystalline polymer, and as a result, it has good drug release characteristics. Examples of such an amorphous polymer include a high molecular weight polymer obtained by ring-opening polymerization of a cyclic dimer of lactic acid and glycolic acid, and a low molecular weight polymer obtained by directly dehydrating and polycondensing them. The common feature of these polymers is that they are both linear polymers.

However, when a high molecular weight polymer among these polymers is used as a DDS base, degradation is unlikely to occur at the initial stage of implantation into a living body, and then it is rapidly degraded by random cleavage of the molecular chain. The release is suppressed only in the initial stage, and thereafter the drug is rapidly released with the decomposition of the base, resulting in irregular release characteristics, which is not preferable as a DDS base. Further, the high molecular weight polymer is generally produced using a catalyst, and the catalyst remains in the base, which is also not preferable as a DDS base.

On the other hand, low molecular weight polymers have been mainly studied recently in order to avoid such disadvantages of high molecular weight polymers. In the case of incorporating a drug using a polymer, the polymer has high hydrophilicity, and the release rate of the drug is higher than the decomposition rate of the polymer.Therefore, a large amount of the drug is released in the initial stage, and only the base remains in the body. There is a problem of remaining. Further, there is a problem that the acid concentration of the polymer is high and causes strong inflammation and the like when implanted in a living body.

As described above, polymers such as lactic acid and glycolic acid have many points to be improved as a biodegradable DDS base, and biodegradable polymers having excellent sustained release characteristics are still present. At present, no polymer has been obtained.

[0008]

Under these circumstances, the present inventors have solved the above-mentioned problems, and have developed a polymer for sustained release of a drug or the like as a release amount, release time, etc. We have made intensive studies to develop a biodegradable polymer that is easy to control the release of and is excellent in biocompatibility. As a result, a polymer obtained by directly dehydrating and / or polycondensing lactic acid and / or glycolic acid in the presence of a sugar alcohol was found to be excellent in the above-mentioned sustained release characteristics, and based on such findings, the present invention was completed. It has been reached.

[0009]

That is, the present invention relates to a method for preparing sugar alcohols from lactic acid and / or glycolic acid in an amount of 1 to 15%.
It was used in the range of weight%, the lactic acid and / or glycolic acid combined direct dehydration polycondensation in the presence of a sugar alcohol of the general formula
(I)

Embedded image Lactic acid and / or the oxy residue of the sugar alcohol represented by
Number average molecular weight of 3 in which polymerized units of glycolic acid are bonded
000 or less biodegradable polymer.

[0010]

The present invention will be described below in more detail. The types of lactic acid and glycolic acid used in the present invention are not particularly limited, and any of D-form, L-form and DL-form can be used for lactic acid. Examples of the type of sugar alcohol include glycerin, trait, erythrit, arabit, adnit, xylit, sorbit, mannitol, idit, talit, zulcit, allozulcit and the like.

In the present invention, the polymer of the present invention is obtained by a direct dehydration polycondensation reaction using these raw materials. Lactic acid and / or
Alternatively, the use ratio of glycolic acid and sugar alcohol is such that the sugar alcohol is in a range of 1 to 15% by weight based on lactic acid and / or glycolic acid. That is, when the use ratio of the two deviates from this range and the amount of the sugar alcohol falls below 1% by weight, the obtained polymer becomes close to the characteristics of the conventional low-molecular-weight linear polymer, and the sustained release is performed as described above. It is not preferable when used as a functional base. Conversely, if the sugar alcohol content exceeds 15% by weight, the resulting polymer becomes a paste from a semi-solid, making it difficult to formulate it, and the polymer is extremely degradable. This range is particularly important in the present invention.

With respect to the method of directly performing a dehydration polycondensation reaction of lactic acid and / or glycolic acid in the presence of a sugar alcohol, a method of carrying out the reaction while introducing nitrogen gas into the mixture of the raw materials, or 2 to 100 mmHg The reaction may be performed under any reduced pressure. At that time, the reaction is carried out at a reaction temperature of 120 to 250 ° C., and the reaction time is not particularly limited depending on the kind of the raw materials used, the proportion used, and the like, but generally requires 2 to 30 hours.

The polymer of the present invention obtained after the reaction is
The reaction is carried out so that the number average molecular weight becomes 3000 or less, and this molecular weight can be easily controlled by the reaction time, the reaction temperature, and the amount of sugar alcohol used. That is,
The shorter the reaction time, the lower the reaction temperature, or the more sugar alcohol used, the lower the molecular weight, and these conditions may be appropriately selected according to the desired physical properties of the polymer. Further, when the molecular weight exceeds 3,000 and deviates from the range of the present invention, the acid residue chain of the polymer becomes longer, so that the characteristics as the polymer base are similar to the characteristics of the low-molecular-weight linear polymer described above. It will be. Furthermore, regarding the lower limit of the molecular weight,
When it is less than 500, the tackiness of the polymer becomes high at room temperature, which makes it difficult to handle, and is not practical because it decomposes in a very short time.

In the present invention, the molecular weight is measured using gel permeation chromatography (GPC). At this time, tetrahydrofuran is used as a solvent, and the column is ultra-styrakel (GPC). Ultrastyragel) (trade name of Waters Co., USA) 100 Å, 1000 Å and 100 Å
Three molecular columns of 00 Å were connected and used, and the molecular weight of the polymer was determined using polystyrene as a standard sample.

The polymers of the present invention which can be obtained in this way is a polymer the molecular chain has become a star shape, the general formula (I)

Embedded image And a polymerization unit of lactic acid and / or glycolic acid bonded to the oxy residue of the sugar alcohol represented by Therefore, the central part is a residue of a sugar alcohol, and the residue of the sugar alcohol is surrounded by a residue chain of lactic acid and glycolic acid. Further, the polymer of the present invention has a feature that, since the terminal of the molecular chain is a hydroxyl group, tissue reactivity at the time of implantation in a living body is low regardless of the molecular weight.

[0016]

EXAMPLES Hereinafter, the present invention will be further described with reference to examples of the present invention, but the present invention is not limited thereto. Also,
In the examples, all percentages are by weight unless otherwise specified.

(Examples 1 to 5) 50 g of DL-lactic acid (90% aqueous solution)
And 0.45 g of D-mannitol in a 200 ml reaction vessel, and introducing nitrogen gas into the mixed solution at a flow rate of 300 ml / min.
The reaction was carried out for 0 hours to obtain a colorless and transparent solid polymer of the present invention. (Example 1)

Further, 0.90 g of D-mannitol (Example 2), 2.25 g
(Example 3), 4.50 g (Example 4) and 6.75 g (Example 5) were reacted in the same manner as above to obtain a colorless and transparent solid polymer of the present invention.

(Comparative Examples 1 and 2) For the purpose of comparison, Example 1 was used.
The reaction was carried out under the same conditions as in Example 1 except that D-mannitol was changed to 0.18 g (Comparative Example 1) and 9.0 g (Comparative Example 2) instead of 0.45 g of D-mannitol, and colorless. A transparent polymer was obtained. The polymer of Comparative Example 1 was in a solid state at room temperature, while the polymer of Comparative Example 2 was in a semi-solid state having strong adhesiveness at room temperature.

Experiment 1 Using the polymers obtained in Examples 1 to 5 and Comparative Examples 1 and 2,
Measurement of molecular weight by these GPC and in vivo (i.
(n vivo) The degradation rate was measured. The in vivo degradation rate was measured by the following method.

First, 50 mg of the polymer was placed in a Teflon tube.
(Inner diameter 2 mmφ, length 70 mm), and heated to 30 to 40 ° C. under a pressure of 100 kg / cm ² to perform a molding treatment. By this treatment, the polymer filled in the Teflon tube is
It became a rod shape with an inner diameter of 2 mmφ. Next, one end of the Teflon tube was used as a pointed end, the tip of the tube was inserted into the subcutaneous region of the back of the rat, and the polymer in the tube was injected and inserted with a stainless rod extruder.

Five weeks after the implantation of the polymer, the rat was sacrificed, the weight of the polymer remaining in the rat was measured, and the decomposition rate was calculated from the weight before the implantation. The results are shown in Table 1.

[0023]

[Table 1] Note) Mn: Abbreviation of number average molecular weight, Mw: Abbreviation of weight average molecular weight

As is clear from the results in Table 1, Examples 1 to
The in vivo degradation rate of the polymer of Comparative Example 5 is lower than that of the polymer of Comparative Example 1, and the polymer of Comparative Example 2 has an extremely high in vivo degradation rate. It turns out that it is not suitable as a polymer.

(Examples 6 to 8) 50 g of DL-lactic acid (90% aqueous solution)
And various sugar alcohols. Examples of sugar alcohols include D-sorbitol (Example 6) and xylit (Example 7).
And erythritol (Example 8), put 2.25 g (5% by weight based on DL-lactic acid) into a 200 ml reaction vessel, and introduce nitrogen gas into the mixed solution at a flow rate of 200 ml / min. 1 at 200 ° C
The reaction was carried out for 0 hours to obtain a colorless and transparent solid polymer of the present invention.

Comparative Example 3 For comparison, the reaction was carried out under the same conditions as in Example 6 except that no sugar alcohol was used, to obtain a colorless and transparent polymer.

Experiment 2 Using the polymers obtained in Examples 6 to 8 and Comparative Example 3, the polymer was formed into a rod by the same molding treatment as in Experiment 1, and this was implanted in the subcutaneous part of the back of a rat for 5 weeks. The rate of in vivo degradation of the eye was determined. The molecular weight of these polymers was measured by GPC and the in vivo degradation rate was measured. The results are shown in Table 2.

[0028]

[Table 2]

As is clear from the results in Table 2, Examples 6 to
The polymer of the present invention reacted with the sugar alcohol of No. 8 has a low in vivo degradation rate in spite of its low molecular weight compared to the polymer not reacted with the sugar alcohol (Comparative Example 3), and is suitable as a biodegradable polymer. You can see that

Reference Example 1 The reaction between DL-lactic acid and D-mannitol was confirmed by measuring a 90 MHz ¹ H-NMR spectrum. Deuterated chloroform of the polymer obtained in Example 4.
The ¹ H-NMR spectrum measured using (CDCl ₃ ) as a solvent is shown in FIG. FIG. 2 shows the ¹ H-NMR spectrum of Comparative Example 3 (polycondensation was performed without using a sugar alcohol).
It was shown to.

When these FIGS. 1 and 2 are compared, the spectrum of FIG. 2 is derived from methyl hydrogen and methine hydrogen of lactic acid.
It consists of peaks at 1.52 ppm (doublet) and 5.21 ppm (quadruple). In addition to these peaks in the spectrum of FIG. 1, peaks derived from methylene hydrogen and methyl hydrogen of D-mannite are present.
(4.31 ppm) and a peak (2.91 ppm) derived from the hydroxyl group at the terminal of the polymer chain. In addition, the composition of the sugar alcohol in the polymer determined from the proton ratio in the spectrum of FIG. 1 almost coincided with the charged composition, and it was confirmed that the reaction between DL-lactic acid and D-mannitol progressed quantitatively. . Further, this was similarly confirmed for other kinds of sugar alcohols or polymers having different use ratios of sugar alcohols.

The sugar alcohol D-mannitol used in Example 4 did not dissolve in deuterated chloroform, but the polymer of the present invention dissolved easily in deuterated chloroform. This confirms that the sugar alcohol has been incorporated into the polymer of the present invention and reacted.

(Examples 9 to 10) 50 g of D-lactic acid (90% aqueous solution)
And Superit 4.50 g (10% by weight based on D-lactic acid) were placed in a 200 ml reaction vessel, and a reaction was carried out at 200 ° C. for 8 hours while introducing nitrogen gas into the mixed solution at a flow rate of 200 ml / min. A colorless and transparent solid polymer of the present invention was obtained. (Example 9)

The same reaction was carried out using 50 g of L-lactic acid (90% aqueous solution) in place of the above D-lactic acid to obtain a colorless and transparent polymer of the present invention. (Example 10)

(Comparative Examples 4 and 5) In order to obtain a polymer having a molecular weight almost the same as that of Examples 9 and 10 without using a sugar alcohol, D-lactic acid (Comparative Example 4) and L-lactic acid (Comparative Example) were used. 5) was performed under the same conditions as in Example 9 except that the reaction time was changed to 3.5 hours.

Experiment 3 Using the polymers obtained in Examples 9 to 10 and Comparative Examples 4 to 5,
The molecular weight of the polymer was measured by GPC in the same manner as in Experiment 1. In addition, the glass transition temperature and the melting point temperature of the polymer were measured by a differential scanning calorimeter (DSC). The results are shown in Table 3. The DSC was measured using a DSC-2 model manufactured by Seiko Denshi Kogyo at a temperature rising rate of 5 ° C./min. Further, the in vivo degradation rate of the polymer in the subcutaneous region of the back of the rat was measured for each predetermined implantation period, and the results are shown in FIG.

[0037]

[Table 3]

As is clear from Table 3, Comparative Examples 4 and 5
D-lactic acid and L-lactic acid alone become crystalline polymers, but the polymer of the present invention reacted with the sugar alcohols of Examples 9 and 10 becomes amorphous and is useful as a DDS base. You can see that. Further, as shown in FIG. 3, the polymers of the present invention of Examples 9 and 10 were substantially the same in molecular weight.
In vivo degradability is significantly lower than that of the polymer of This is considered to be mainly a difference based on the structure of the polymer main chain, that is, a difference between the star shape and the linear shape of the polymer molecular chain.

(Example 11) 42.05 g of L-lactic acid (90% aqueous solution)
(0.42 mol), 13.69 g (0.18 mol) of glycolic acid and 2.58 g of D-sorbit were placed in a 200 ml reaction vessel, and nitrogen gas was introduced into the mixed solution at a flow rate of 150 ml / min at 190 ° C. for 16 hours. The reaction was performed to obtain a colorless and transparent solid polymer of the present invention.

Comparative Example 6 For comparison, the reaction was carried out under the same conditions as in Example 11 except that no sugar alcohol was used, to obtain a colorless and transparent polymer.

Experiment 4 Using the polymers obtained in Example 11 and Comparative Example 6, the molecular weight of the polymer was measured by GPC in the same manner as in Experiment 1. Further, using these polymers, the polymer was formed into a rod by the same molding treatment as in Experiment 1, and this was implanted in the subcutaneous region of the back of a rat, and the in vivo degradation rate at 5 weeks was determined. Table 4 shows the results.

[0042]

[Table 4]

[0043]

As described above, since the biodegradable polymer of the present invention is polymerized in the absence of a catalyst and is obtained by reacting the polymer with a sugar alcohol, impurities such as a catalyst, etc. No removal operation is required, and thus the resulting polymer does not contain impurities such as organic solvents and is preferred as a biomedical DDS base.

In addition, the obtained polymer has a star-shaped molecular chain, and although it has a low molecular weight, it is possible to obtain a polymer having low decomposability over a long period of time. Furthermore, due to the low molecular weight of the polymer, the polymer is obtained as a solid with a low softening point, which means that when mixing the polymer of the invention with the drug, the operation can be carried out at room temperature or under slight heating. Thus, problems such as decomposition and denaturation of the drug can be avoided.

Furthermore, since the residue at the terminal of the molecular chain of the polymer of the present invention is a hydroxyl group, tissue reactivity at the time of implantation into a living body is low, and this tendency is particularly remarkable in the early stage of implantation into a living body.
Therefore, the polymer of the present invention can be used as a DDS base for complexing with various drugs, and examples of such drugs include hormones, antihistamines, antihypertensives, vasodilators, vasodilators, and stomachs. Digestives, intestinals, contraceptives, germicidal disinfectants for skin, agents for parasitic skin diseases, antiphlogistics, analgesics, bile drugs, antirheumatic drugs, inotropics, hemorrhoids, constipation
Vitamin preparations, various enzyme preparations, vaccines, antiprotozoal agents, interferon-inducing substances, anthelmintics, fish disease drugs, pesticides, auxins, plant hormones such as gibberellins, cytokinins, abscisic acid, and insect pheromones. These drugs can be used whether they are natural products or synthetic products.

The case where the utility of the polymer of the present invention is used as a DDS base has been described above. Those which require sustained release, such as antibacterial agents, antifungal agents, food additives, fragrances, pesticides, etc. Of course, it can be used as a sustained-release base.

[Brief description of the drawings]

FIG. 1 is a diagram showing a ¹ H-NMR spectrum of a polymer of the present invention obtained in Example 4.

FIG. 2 is a diagram showing a ¹ H-NMR spectrum of a polymer obtained in Comparative Example 3.

FIG. 3 shows the in vivo degradation rate of the polymer of the present invention obtained in Examples 9 to 10 and the polymers obtained in Comparative Examples 4 to 5 every predetermined period when the polymer is implanted in the subcutaneous part of the back of a rat. FIG.

Claims (1)

(57) [Claims] A sugar alcohol is used in an amount of 1 to 15% by weight based on lactic acid and / or glycolic acid, and lactic acid and / or glycolic acid is directly dehydrated and polycondensed in the presence of the sugar alcohol to obtain a compound represented by the general formula ( I) Lactic acid and / or the oxy residue of the sugar alcohol represented by
Number average molecular weight of 3 in which polymerized units of glycolic acid are bonded
000 or less biodegradable polymer.