JPH01163135A - Sustained release base - Google Patents

Abstract

PURPOSE:To obtain a sustained release base having a proper softening point, showing biodegrading properties, comprising a polymer prepared by reacting a polymer or copolymer of lactic acid and/or glycolic acid with a polyhydric alcohol or polyethylene glycol. CONSTITUTION:A sustained release base comprising a polymer prepared by directly condensing lactic acid and/or glycolic acid through dehydration, e.g., under reduced pressure to give a polymer or copolymer and reacting the polymer or copolymer with a polyhydric alcohol (e.g., ethylene glycol or pinacol) or polyethylene glycol. This sustained release base has especially excellent biodegrading properties and can control release of drug to organism. The base is useful as an implanting material for organisms by blending with hydroxyapatite, retaining material for cells and microorganisms, carrier as microcapsule, soil improver, degradable agricultural film, quality improver for fruits, gas separating permeable film, aroma, surfactant, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a sustained release base, and particularly to a base that has excellent biodegradability and is capable of controlling the release of a drug into a living body.

(Prior Art) Polymers such as lactic acid and glycolic acid are biodegradable and bioabsorbable, and have thus far been applied to biodegradable medical materials such as surgical sutures.

In addition, in recent years, drug release control systems (DDS) have been developed to control drug administration to living organisms.
Various studies are being carried out as a base material for the erythrium pyrolysis system.

In this way, the DS base has the function of releasing a certain amount of drug into the body over a predetermined period of time. A base of pure ingredients is desired.

Conventionally known polymers such as 1L acid and glycolic acid are desired to have a high molecular weight in order to prolong the sustained release period, and polymerization has been carried out using lactide and glycol 1- as raw materials.

However, since this product has a high molecular weight, the base is solid, and therefore, when mixing it with drugs, it is necessary to melt the base at high temperature, which causes problems such as denaturation and decomposition of the drug. occurred.

On the other hand, using lactic acid and glycolic acid as raw materials, we perform dehydration polycondensation without a catalyst to create low molecular weight polymers! 5 methods are also conventionally known.

However, although this product has a low molecular weight and avoids the problems of drug denaturation and decomposition mentioned above, it contains a large amount of lactic acid and glycolic acid monomers and oligomers, and has a high acid value, so it is irritating to living tissues. Not only does it become stronger and become a problem, but depending on the type of drug used, it may cause denaturation of the drug when mixed with the drug or stored.

Furthermore, this product biodegrades too quickly and has almost no function as a sustained release base.

On the other hand, a method is known in which a polymer is softened by obtaining a copolymer of a polymer such as 1L acid or glycolic acid and a lactone or a hydroxycarboxylic acid such as α-oxybutyric acid or α-oxyvaleric acid. .

(JP-A-47-2032B) However, this material is not preferable as a biodegradable sustained release base because its degradability in vivo is lower than that of a homopolymer such as 1L acid.

As described above, a sustained release base made of polymers such as lactic acid and glycolic acid that has good miscibility with drugs, etc., is non-irritating to living tissues, and has excellent biodegradability has yet to be found. The current situation is that this has not been done.

(Problems to be Solved by the Invention) In order to solve the above-mentioned problems, the present inventors have sought to obtain a sustained-release base that is biodegradable, has no side effects on living organisms, and is We have carried out extensive research in order to obtain an excellent base that can be used in a wide range of applications without any restrictions on drug decomposition or sustained release control.

(Means for solving the problem) As a result, a polymer obtained by reacting a polymer or copolymer of lactic acid and/or glycolic acid with a polyhydric alcohol or polyethylene glycol has an appropriate softening point, We have discovered that it is excellent as a biodegradable sustained release base, and have completed the present invention based on this knowledge.

That is, the present invention relates to a sustained release base obtained by reacting a polymer or copolymer of lactic acid and/or glycolic acid with a polyhydric alcohol or polyethylene glycol.

(for production) The present invention will be explained in more detail below.

The polymer or copolymer of lactic acid and/or glycolic acid of the present invention may be any polymer or copolymer as long as it is produced by a method that does not require a boat.

For example, γLN! A polymer or copolymer can be obtained by directly dehydrating and polycondensing glycolic acid under reduced pressure. (Yubara et al., Koka, 68(5), 983(
1965) Also, after distilling lactic acid and glycolic acid under reduced pressure in the presence of a catalyst such as zinc oxide to obtain lactide and glycolide, these are subjected to a polymerization reaction in the presence of a catalyst such as tetraphenyltin and stannous chloride. It can also be manufactured by (Kulkarni, J., Biomed, Ma.
Ter, Res...! L, 169 (1971)) Furthermore, the lactic acid monomer used in these cases may be any of the 0-form, L-form, and DL-form.

In the present invention, the number average molecular weight of the lactic acid and/or glycolic acid polymer or copolymer obtained in this manner is 300 to 300.
10.000 is used.

In this case, if the molecular weight of these polymers deviates from this range and falls below 300, monomers and oligomers of lactic acid and glycolic acid will be polymerized, resulting in a high acid value even after the reaction with polyhydric alcohols, etc. described below. , which becomes a problem as it becomes more irritating to living tissues.

Conversely, if the molecular weight is less than 10,000, the effects of the present invention cannot be obtained even if the reaction with a polyhydric alcohol or the like described below is performed.

As the type of polyhydric alcohol, dihydric alcohols such as ethylene glycol, propylene glycol, trimethylene glycol, pinacol, and trihydric alcohol such as glycerin can be used.

Moreover, the polyethylene glycol used has a number average molecular weight of approximately 150 to 10,000.

The type of polyhydric alcohol used in the present invention is not particularly limited to these, but the polyhydric alcohol and polyethylene glycol used have a melting point of about 70°C or less.

The ratio of the lactic acid and/or glycolic acid polymer or copolymer to the polyhydric alcohol or polyethylene glycol is such that the equivalent ratio of the polyhydric alcohol or polyethylene glycol to the 1L acid and/or glycolic acid polymer is from 0.3 to Use at a ratio within the range of 5.0.

In addition, these equivalent ratios are based on the number of carboxyl groups (average) at the end of the polymer chain in the case of lactic acid and/or glycolic acid polymers, and are based on the number of hydroxyl groups (average) in the case of polyethylene glycol. )based on.

Regarding the method of conducting the reaction using these raw materials,
First, the monoacid and/or glycolic acid polymer or copolymer to be used is heated to the softening temperature of 100 to 250°C.
The mixture is heated and melted, and a polyhydric alcohol or polyethylene glycol is added thereto to carry out a reaction.

The reaction is carried out under the introduction of nitrogen gas, and the reaction time is the f
Although the reaction time is not limited and varies depending on the molecular weight of the L acid polymer, the type of polyhydric alcohol, etc., the reaction time is approximately 11 to 10 hours.

Another method is when heating and melting!・Use toluene, benzene, etc. as a dehydrating agent, or use 10 to 100 m
The reaction can also be carried out under reduced pressure of about mHg.

The base of the present invention obtained after the reaction differs depending on the component composition of the raw materials, but since it is usually in a paste form, it is possible to add and mix the drug at room temperature or under slight heating. .

Therefore, polypeptides such as vascular growth factors, anticancer drugs, drugs such as interferon, etc. are not altered by heating when mixed with the base, and are held in a stable state in the base.

Since the base of the present invention has excellent characteristics as a sustained release base, it can be used not only as a base for DDS of drugs, but also as an implant material for living organisms mixed with hydroxyapatite etc., for bacterial cells, Its applications are wide-ranging, including microbial retention agents, carriers as microcapsules, soil conditioners, collapsible agricultural films, fruit quality improvers, gas separation permeable membranes, aromatics, and surfactants. be.

(Example) The present invention will be further explained below with reference to Examples, but the present invention is not limited thereto.

In addition, all percentages indicate xi% unless otherwise specified.

Example 1 Internal volume 100m1 equipped with a thermometer, nitrogen inlet pipe, and exhaust port
In a reactor, IJ-di-
20 g of lactide and 14 g of glycerin (98.5%, reagent manufactured by Raiyu Yakuhin Kogyo 0 (Ten)) were added, and the mixture was immersed in an oil path at 215°C.

A nitrogen gas flow rate of 100 ml/min was introduced into the reaction vessel, and the reaction was carried out for 5 hours.

The acid value of the paste-like sustained release base of the present invention obtained after the reaction was measured based on the acid value measurement method of JIS K6901 (liquid unsaturated polyester resin test method).

In addition, by lH-NMR, the glycerin terminal group
The presence or absence of reactivity was confirmed by the shift of the peak derived from 2-0-.

Furthermore, in order to investigate the softening point of the base material of the present invention, approximately 0.5 g of
was created on a copper plate, and the temperature was gradually raised to determine the temperature at which stringing began with a glass ball, and this was taken as the softening point temperature.

These results are shown in Table 1.

For comparison, the same reaction was carried out using 2.7 g of D-mannite (Kiyu Yakuhin Kogyo (Wa reagent)) instead of the glycerin. (Comparative Example 1) This comparative example The acid value and softening point of the product and the unreacted poly dl-lactide were measured in the same manner as above, and the results are shown in Table 1.

Example 2 Internal volume 300m1 equipped with thermometer, nitrogen inlet pipe, and exhaust port
80 g of poly-L-lactide with a number average molecular weight i of 3,100 was placed in a reactor and immersed in an oil path at 195°C.

After melting the poly-L-lactide, 3.2 g of ethylene glycol (reagent manufactured by Wako Tsumugi Pharmaceutical Co., Ltd.) was added thereto, and nitrogen gas was introduced into the reaction vessel at a flow rate of 150 m1/win.
A time reaction was performed.

In addition, in place of the above ethylene glycol, 3.9 g of propylene glycol (reagent manufactured by Wako Pure Chemical Industries Ltd.), 1.8
-7.5 of octanediol (Wako Tsumugi Kogyo @Shire Reagent)
A similar reaction was carried out using g.

S2 of the wax-like sustained release base of the present invention obtained after the reaction
The value and softening point temperature were measured in the same manner as in Example 1, and 'H
The presence or absence of reaction of the end groups was confirmed by -NMR, and the results are shown in Table 2.

Furthermore, the acid value and softening point of poly-L-lactide which was not subjected to the reaction were measured in the same manner, and the results are also shown in Table 2.

Table 2 Example 3 Into the same reactor as in Example 2, 60 g of L-lactic acid-glycolic acid copolymer (L-lactic acid content: 46 mol%) with a number average molecular weight of 1 and 800 was added. A predetermined amount of polyethylene glycol (reagent manufactured by Wako Pure Chemical Industries, Ltd.) of each molecular weight shown in 1 was added.

This was immersed in an oil path at 210°C, and a reaction was carried out for 6 hours while introducing nitrogen gas into the reactor at a flow rate of 130 ml/win.

The acid value and softening point temperature of the paste-like sustained release base of the present invention obtained after the reaction were measured in the same manner as in Example 1, and IH-
N) -CH2 derived from polyethylene glycol by IR
The presence or absence of reaction of the -0- group was confirmed, and the results are shown in Table 3.

Furthermore, the acid value and softening point of the unreacted LIL acid-glycolic acid copolymer were similarly measured, and the results are also shown in Table 3.

Table 3 Example 4 In the same reactor as Example 2, number average molecule i 3 , 600
30 g of poly-lactide with a number average molecular weight of 7,50
0 polyethylene glycol (reagent manufactured by Wako Tsumugi Pharmaceutical Co., Ltd.)

116,000) of 62.5K was added.

5. This was immersed in an oil path at 220°C, and nitrogen gas was introduced into the reactor at a flow rate of 220 ml/min.
The reaction was carried out for 5 hours.

After the reaction, 91 g of the sustained release base of the present invention in the form of white wax was obtained, which was water-soluble and had surface activity.

The acid value and softening point temperature of this base were measured in the same manner as in Example 1, and the presence or absence of reaction of the terminal group was confirmed by 'H-NMR. These results are shown in Table 4.

Furthermore, the acid value and softening point of poly-L-lactide which was not subjected to the reaction were measured in the same manner, and the results are also shown in Table 4.

Patent applicant: Taki Chemical Co., Ltd.

Claims (1)

[Claims] A sustained release base obtained by reacting a polymer or copolymer of lactic acid and/or glycolic acid with a polyhydric alcohol or polyethylene glycol.