JPH02212436A - Sustained release base - Google Patents

Abstract

PURPOSE:To obtain a sustained release base, consisting of a polymer prepared by carrying out direct dehydrating polycondensation of lactic acid and/or glycolic acid with a specific hydroxycarboxylic acid, excellent in release control characteristics of a drug and capable of avoiding decomposition of the drug in molding without side effects on living bodies. CONSTITUTION:A sustained release base consisting of a copolymer, prepared by carrying out direct polycondensation of (A) lactic acid and/or glycolic acid with (B) a hydroxycarboxylic acid expressed by formula I [R' is CH2CH3, CH(CH3)2, CH2-CH(CH3)2, formula II or III; R'' is H or CH3] [e.g. alpha- hydroxybutyric or valic acid (alpha-hydroxy-isovaleric acid)] in the absence of a catalyst at 120-250 deg.C temperature under 10-100mmHg reduced pressure while introducing nitrogen gas and having 500-5000 number-average molecular weight at (10/90)-(90/10) molar ratio of the ingredients (A/B). Since the above-mentioned copolymer is a solid with a low softening point. mixing thereof with a drug can be carried out at ordinary temperature or while somewhat heating and problems of decomposition and denaturation of the drug are avoided.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a biodegradable sustained release base having a sustained release function.

(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; DrBDe) have been developed to control drug administration to living organisms.
Various studies are being conducted as a base material for the Livery System.

As such, it is desirable for the DS base to release a certain amount of drug into the living body over a predetermined period of time, and to quickly decompose in the living body after the drug is released.

Furthermore, for living organisms, it is desired that the base contains no impurities and has pure ingredients without the risk of side effects.

Conventionally known bases include homopolymers such as lactic acid and glycolic acid. However, homopolymers such as lactic acid and glycolic acid are used in surgical sutures, etc., and as a result, products with high molecular weight are generally desired.
Polymerization is carried out using lactide or glycolide as a raw material and using a catalyst. Therefore, in this method, it is necessary to remove the catalyst remaining as an impurity, and an organic solvent is used for removing the catalyst, but a new problem arises, that is, the remaining organic solvent. Furthermore, since the polymer has a high molecular weight, it is in a solid state, and therefore, when mixing it with a drug, it is necessary to melt the base at a high temperature, which causes problems such as denaturation and decomposition of the drug.

On the other hand, lactic acid and glycolic acid are used as raw materials and dehydrated without catalyst! A method is known in which a low molecular weight homopolymer is obtained by performing i-polycondensation. This method allows a low molecular weight polymer to be obtained, the temperature during the above-mentioned molding can be lowered, and drug decomposition is suppressed. However, as with the above-mentioned high molecular weight homopolymers, the above-mentioned polymers are generally crystalline and have the following problems as DDS bases for biological use. In other words, such crystalline polymers show non-uniform degradability in vivo. This is because crystalline polymers consist of a crystalline part and a non-quality part, and the crystalline part is smaller than the non-quality part. This is due to extremely poor biodegradability. In addition, drugs are generally dissolved or dispersed in non-quality parts rather than in crystalline parts, so when this is used as a DDS substrate, the non-quality parts decompose first and release of the drug ends. Although it is possible to reduce this crystallinity to some extent by lowering the molecular weight, which is undesirable as a DDS base because a crystalline portion that does not contain the drug remains after the treatment, it is generally possible to reduce the molecular weight to a few hundred or less. It is necessary to do so. Furthermore, in this case, the acid concentration at the end of the polymer becomes high, causing problems such as inflammation when it comes into contact with a living body, and biodegradability is too rapid, making it unsuitable as a sustained release base.

In addition, in order to solve the problems of biodegradability and sustained release caused by the crystallinity of such polymers, we are considering synthesizing a non-grade polymer by copolymerizing lactic acid and glycolic acid and applying it as a base material for DDS. However, problems still remain, including with the high molecular weight polymers mentioned above. In other words, when a drug is incorporated into these biodegradable polymers, the drug release rate is higher than the decomposition rate of the base polymer. Remains in the body.

Furthermore, a polylactide base for topical administration of pharmaceuticals consisting of lactic acid and oxycarboxylic acid is known, but this uses molecular cyclic esters such as lactide or glycolide as raw materials and a reaction is carried out using a catalyst. As a result, there remains the problem that the catalyst that becomes an impurity remains, and the biodegradability of the polymer due to its high molecular weight remains, which poses problems as a divisor base.

As described above, polymers such as lactic acid and glycolic acid currently have many points to be improved as biodegradable DDS bases, and there are still no suitable biological DDS bases that can replace these. The current situation is that it has not been discovered.

(Problems to be Solved by the Invention) In view of the above-mentioned problems, the present invention provides a DDS base for living organisms that has excellent drug release control characteristics and that has no side effects on living organisms. The object of the present invention is to provide an excellent sustained-release base that has good moldability and can be applied to a wide range of applications, avoiding the problem of drug decomposition during molding.

(Means for Solving the Problem) As a result of the present inventors' earnest efforts, a polymer of a specific composition obtained by direct dehydration polycondensation of lactic acid and/or glycolic acid and an oxycarboxylic acid having a specific structure is We have discovered that this is an excellent DDS base for living organisms that solves the problems, and have completed the present invention.

That is, the present invention provides lactic acid and/or glycolic acid (A> and -
Maximum (+) HO-C-COOH (1) R" However, Ro is cH, -CL -, (CHz)z-CL,
(CI+, >2-CI+C1], obtained by direct dehydration polycondensation of oxycarboxylic acid 1tQ (B) represented by - (B)/(A) molar ratio 10/90 to 90/10, number average molecular weight 500 The gist is a polymer consisting of ~5000.

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

There is no particular limitation on the type of lactic acid used in the present invention, and it may be any of the 0-form, L-form, and DL-form. -oxybutyric acid (2-l+ydroxy-n-bu
Lyric acid), Valic acid (α-bydro
xy-iso-valerric acid), leucine acid (a-hydroxy-iso-caproi
e acid), mandelie
acid), atrolactic acid (aLro-1actie
acid), 3-phenyl lactic acid (3phenyl-1a
cticacid).

In the present invention, these raw materials are used and the base material of the present invention is obtained by direct dehydration polycondensation reaction. Regarding the proportion of both materials used, the copolymer obtained after direct dehydration polycondensation reaction is based on lactic acid and/or glycol a(A). and the oxycarboxylic acid (B
) molar ratio (B)/(A> is 10/90 to 90/
It is used in proportions that are within the range of 10.

In this case, if the molar ratio is less than 10/90 and lactic acid or glycolic acid is used extensively, the crystallinity of the polymer will increase and the mixture of this polymer base and drug will form a non-uniform matrix. This is not preferable as a sustained release base because the drug release rate increases.On the other hand, if the molar ratio is less than 90/10 and oxycarboxylic acid is used extensively, the crystallinity of the polymer increases as described above. Not only this, but also the biodegradability of the polymer is extremely reduced, making it undesirable as a biodegradable DDS base.

Regarding the direct dehydration polycondensation reaction between lactic acid, glycolic acid and oxycarboxylic acid, the reaction may be carried out without a catalyst while introducing nitrogen gas into the mixture of the raw materials, or 1.
The reaction may be carried out under a reduced pressure of about 0 to 10 (lvHFl), and the reaction temperature is 120 to 250°C, and the reaction time is 2 to 30°C. It takes time.

In the present invention, it is necessary that the number average molecular weight of the polymer base obtained after the reaction is in the range of 500 to 5000, but this molecular weight range can be easily adjusted by selecting the reaction time described above. Can be done.

To explain this molecular weight range in more detail, if the molecular weight of the copolymer deviates from this range and falls below 500, the release of the drug to be added and mixed becomes extremely rapid.

It has no function as a slow-dispersing base.

Conversely, if the number average molecular weight is less than 5000, the softening point of the resulting copolymer will be high, which will require heating at high temperatures when mixing with drugs or molding, which may cause problems such as drug decomposition. In addition, the dispersion state of the drug becomes non-uniform, and as a result, the drug release rate is conversely higher than that of a copolymer of 5000 or less, and only the copolymer base remains for a long period of time.

(Example) Hereinafter, the present invention will be further explained with reference to the attached drawings by presenting examples of the present invention, but the present invention is not limited to these, and unless otherwise specified, all percentages are by weight. shows.

Examples 1 to 6 L-Rei 1i! (90% aqueous solution) and DL-valine n<crystal) mixture (L-lactic acid/DL-valine acid = 70/30 (mole ratio)) was put into a 200 ml reaction vessel,
The reaction was carried out at 200° C. for 10 hours while introducing nitrogen gas into the mixture at a flow rate of 0 ml/win to obtain a copolymer that was solid at room temperature (Example 1).

Also, instead of DL-valic acid, DL-α-oxybutyric acid (
Implementation IM2>, DL-Leucic Acid (Example 3), DL-
The reaction was carried out under the same conditions as in Example 1, except that Mandel vi (Example 4), DL-atrolactic acid (Example 5), and L-3-phenyllactic acid (Example 6) were used, and all of them were solid. A copolymer of was obtained.

Comparative Examples 1 to 3 For comparison, instead of valic acid in Example 1, 3-
(p-hydroxyphenyl)propionic acid (3(P-
hydroxyphenyl) propionic
acid) (comparative Ml), DL-β-oxybutyric acid # (comparative example 2), α-hydroxyisobutyric acid (α-hydroxyisobutyric acid)
A solid copolymer was obtained by carrying out the reaction under the same conditions except that isobutyric acid (Comparative Example 3) was used.

Experiment 1 Physical properties of these copolymers and in vivo
) Degradation rate was measured. Incidentally, the in vivo decomposition rate was determined by the following method.

First, a predetermined amount of copolymer was placed in a Teflon tube (inner f1
2smφ, length 50I), 100kf/cs
The molding process was carried out at 70°C under a pressure of
The tip of the tube, which had become a rod with a diameter of φ, was inserted into the lower back skin of the rat, and the tube was injected using a stainless steel rod-shaped pusher.

After implanting the copolymer, rats were sacrificed by mouth for 5 weeks, the weight of the remaining copolymer was measured, and the decomposition rate was calculated from the weight before implantation. The results are shown in Table 1.

As is clear from Table 1, Comparative Examples 1 to 3 all have a number average molecular weight of 500 or less, and have extremely high in vivo decomposition rates and inferior sustained release performance compared to the Examples of the present invention.

Examples 7 to 10 The mixing molar ratio of glycolic acid and L-leucic acid (glycol a/L-leucic acid molar ratio) was 90/10 (Example 7), 50150 (Example 8), and 30/70 (Example 8), respectively. Example 9), mixed so as to be 10/90 (Example 10),
50 g of each was placed in a 200@1 volume reaction vessel.

A copolymer was obtained by carrying out a reaction at 200° C. for 10 hours while introducing nitrogen gas into this mixture at a rate of 200 MZ/win.

Comparative Examples 4 and 5 Glycolic acid and L-leucic acid were mixed so that the mixing molar ratio (glycolic acid/L-leucic acid molar ratio) was 9515 (Comparative Example 4) and 5/95 (Comparative Example 5), respectively. , 501F were similarly placed in each 200 d capacity reaction vessel.

Similarly, nitrogen gas was added to this mixture at 200 mt'/sin.
A copolymer was obtained by conducting a reaction at 200° C. for 10 hours while introducing the copolymer at a ratio of .

Experiment 2 These copolymers were shaped into rods by the same molding process as in Example 1, and implanted under the skin of the backs of rats for 5 weeks to determine the rate of oral decomposition.

Table 2 shows the physical property measurement results and in vivo decomposition rates of these copolymers.

As is clear from Table 2, in Comparative Example 4.5,
The ratio of glycolic acid and oxycarboxylic acid is 10/90
~90/10, compared to the present invention.
The v+vo decomposition rate is extremely low, making it unsuitable as a sustained release base.

Examples 11 to 13 Mixing molar ratio of D-lactic acid (90% aqueous solution) and DL-mandelic acid (D-lactic acid/DL-mandelic acid molar ratio) is 70/3
0 (Example 11), 50150 (Example 12), 30/
70 (Example 13), and 50 g of the mixture was placed in each 200 mf reaction vessel.

This mixture was reacted at 200° C. for 12 hours while introducing nitrogen gas into the mixture at a flow rate of 200 yal/soin to obtain a copolymer and a homopolymer.

Comparative Examples 6 and 7 In order to obtain a homopolymer of D-lactic acid, 60% of D-lactic acid was
g (Comparative Example 6), and 30 g of DL-mandelic acid (Comparative Example 7) to obtain a homopolymer of DL-mandelic acid.
were similarly placed in each 200 mZ capacity reaction vessel.

Similarly, this mixture was reacted at 200° C. for 12 hours while introducing nitrogen gas into the mixture at a flow rate of 200+*1/sin to obtain a copolymer and a homopolymer.

Experiment 3 These polymers were shaped into rods by the same molding process as in Example 1, and implanted under the skin of the back of a rat for 7 weeks to determine the decomposition rate.

Table 3 shows the physical property measurement results and in vivo decomposition rates of these copolymers.

As is clear from Table 3 of Table 3, Comparative Examples 6 and 7 both had i
The n-vivo decomposition rate is low, making it unsuitable as a sustained release base.

Examples 14 to 17 50 g of a mixture of DL-lactic acid (90% aqueous solution) and DL-leucinic acid (DL-lactic acid/DL-leucinic acid = 50150 (mole ratio)) was placed in a 200 ml reaction vessel, and
At 200° C. for 4 hours (Example 14) and 8 hours (Example 1) while introducing nitrogen gas into the mixture at a flow rate of m1/win.
5), 12 hours (Example 16), 18 hours (Example 17)
) was reacted to obtain a copolymer.

Comparative Example 8.9 For comparison, only the reaction time was 3 hours (Comparative Example 8)
, 30 hours (Comparative Example 9).

Experiment 4 A similar experiment was conducted, and the results of measuring the physical properties of these copolymers are shown in Table 4. In addition, in the lower back skin of rats
The in vivo degradation rate is shown in Figure 1.

Table 4 As is clear from Table 4, it can be seen that a copolymer with a desired molecular weight can be easily obtained by adjusting the reaction time.

Moreover, as shown in FIG. 1, if the molecular weight is outside the range of the present invention, it will not have the function as a sustained release base.

Example 18 Each 45-2 of the copolymer of glycolic acid and L-leucic acid obtained in Examples 7 to 10 and Comparative Example 4.5 was combined with natural luteinizing hormone-releasing hormone (!utein) as a drug.
Ising hor@one releasing
hormone (hereinafter abbreviated as LH-RH), the amino acid sequence of natural LH-RH is pGUn-His-Tr.
p-9erTyr-Leu-A, rg-Pro-Gly
-NH2) were placed in glass test tubes, and mixed and stirred at a temperature of 80°C for 2 minutes.

After cooling the mixture, it was filled into a disposable type Teflon tube (inner diameter 21 mIIφ, length 60111 J), and molded at a temperature of 50°C for 2 minutes under a pressure of 100 kg/am'. Through this process, the composite filled in the Teflon tube has an inner diameter of 2III*φ and a length of 1
゜It became a thin rod shape.

In order to sterilize this molded composite, it was heated to ``C'' at a temperature of -78℃ (dry ice - methanol) in a nitrogen atmosphere.
Gamma rays from an o-ray source were irradiated for 3 hours at a line I rate of I x 10' R/b.

The in vivo release amount of the drug (physiologically active substance) from the complex obtained by the above treatment was measured.

The method was to test the complex in Wistar rats (male, body weight: 40
The tip of a disposable type Teflon tube was inserted into the lower part of the back skin weighing 0 to 500 g), and the entire amount of the filled composite was extruded with a Teflon rod and inserted.

After a predetermined period of time had elapsed, the rats were sacrificed, the complex was extracted, the amount of remaining drug was measured, and the drug release rate was calculated from the injected amount.

In this way, the amount of drug released for each drug was measured at each predetermined period, and the results are shown in FIG.

Example 19 Each of the copolymers 451 of DL-lactic acid and DL-leucic acid obtained in Examples 14 to 17 and an LHH analogue [
5 mg of des-Gly'', D-Leu']-LH-RH were each placed in a glass test tube, and mixed and stirred at a temperature of 70°C for 3 minutes.These complexes were placed in a Teflon tube by the same procedure as in Example 18. Inner diameter 21φ, length 10
It was molded into a rod shape with a diameter of
Irradiation was performed for 1 hour at a dose rate of X 10'R/h.

The complex thus obtained was implanted into the lower back skin of a rat, and the pharmacological effect of the drug was determined as the weight of prostatic defoliation per 1001 rat body weight (B/100 gbw), and the results are shown in Figure 3. Ta.

(Effects of the Invention) As described above, since the sustained release base of the present invention is obtained by reacting without a catalyst, there is no need for a special catalyst removal operation, and therefore the obtained copolymer is It is preferable as a DDS base for living organisms that does not contain impurities such as solvents.

Furthermore, since the obtained polymer is in a solid state with a low softening point, it can be mixed with a drug at room temperature or under slight heating, thereby avoiding the problems of decomposition and denaturation of the drug.

Furthermore, despite having a wide molecular weight range, this polymer has a completely non-polymer composition and has optimal sustained release properties for controlled drug release. Therefore, the base of the present invention can be applied to a wide variety of drugs, such as hormones, antihistamines, antihypertensives, vasodilators, vascular reinforcing agents, digestive aids, and more! Intestinal agents, contraceptives, sterilizing agents for the skin, agents for parasitic skin diseases, anti-inflammatory agents, analgesics, choleretic agents, antirheumatic drugs, cardiotonic agents, hemorrhoid treatment agents, constipation treatment agents, vitamin preparations, various enzyme preparations Drugs such as vaccines, antiprotozoal agents, interferon inducers, anthelmintics, fish disease drugs, agricultural chemicals, plant hormones such as auxin, gibberellin, cytokinin, and apsidic acid, and insect pheromones can be used. Further, these drugs may be either natural products or synthetic products.

[Brief explanation of the drawing]

FIG. 1 is a graph showing the relationship between the biodegradation rate and the in-vivo implantation period of Examples 14 to 17 of the present invention and Comparative Examples 8.9, and FIG. and comparative example 4
．． FIG. 3 is a graph showing the relationship between the in-vivo release amount of the drug from the complex consisting of 5 and the in-vivo implantation period, and FIG. FIG. 2 is a graph showing the relationship between the effect (expressed as the weight of prostatic delobation) and the period of in-vivo implantation.

Claims (1)

[Claims] Lactic acid and/or glycolic acid (A) and general formula (I)▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) However, R' is CH_3-CH_2-, (CH_3)_2
-CH-, (CH_3)_2-CH-CH_2-, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, and R" is H- or the oxyoxygen represented by CH_3- A sustained release base obtained by direct dehydration polycondensation with carboxylic acid (B) and having a molar ratio of (B)/(A) of 10/90 to 90/10 and a number average molecular weight of 500 to 5000.