JP2709516B2 - Medical composition - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a medical composition, which is a composition for inducing osteogenesis by controlling the release of an osteogenic factor in a living body, and further comprising a bone composition. It relates to an excellent medical composition that splits in vivo with its formation.

(Prior Art) In orthopedic surgery, oral surgery, and the like, when a bone defect in a living body caused by trauma, excision, or the like is to be prosthetic, autologous bone transplantation has been conventionally performed.

This is due to better engraftment to the transplant bed than performing allogeneic bone transplantation or xenogeneic bone transplantation. However, autologous bone grafting has a limited amount that can be collected, and has drawbacks such as the risk of infection and the prolonged pain of patients due to the formation of new surgical wounds for bone graft acquisition.

As an alternative to autologous bone grafting, there is a method of using a metal such as stainless steel or a titanium alloy as an artificial biomaterial,
Due to the remarkable development of biomaterials, they have been used because of their availability.

However, in the method using these artificial biomaterials, the material strength is excellent, but the affinity with the living tissue is poor.

As a method of improving this point, such a material surface is coated with hydroxyapatite or the like, and a surface treatment with a biocompatible material is performed to improve the affinity with surrounding tissues. Not something.

On the other hand, as biocompatible materials, biodegradable polymers such as polylactic acid, lactic acid-glycolic acid copolymer, polyglycolic acid, poly β-hydroxybutyrate, and polyε
Polymer materials such as aliphatic polyesters such as caprolactone, or copolymers thereof with hydroxyaromatic carboxylic acids, and materials obtained by complexing these polymer materials with hydroxyapatite and tricalcium phosphate have been studied.

However, these materials have reduced mechanical strength during hydrolysis in the living body and cause fatigue deterioration, and have little effect on bone formation, and are merely harmful to tissues in terms of biocompatibility. Just no material.

Under these circumstances, mouse is used as a bone forming material.
Dunn osteosarcoma, a biologically active substance that differentiates and proliferates osteogenic cells and chondrocytes isolated from human osteosarcoma, or human bone,
Bovine bone, a substance obtained by genetic modification, that is, an osteogenic material using a complex of bone morpho genetic protein and collagen has been proposed. However, when collagen is used, since collagen is a material derived from a natural product, its molecular weight, amino acid composition,
Since the amount of water retention is not constant, and it is difficult to completely remove the telopeptide portion having antigenicity,
A foreign body reaction occurs in the living body, and the bone forming factors are poorly phagocytosed by foreign body giant cells and other phagocytes, and the bone forming ability is not sufficiently expressed.

In addition, a medical material in which a drug is contained in a material such as polylactic acid or polyglycolic acid instead of collagen is known.

However, according to this polylactic acid or the like, it is necessary to perform heat melting and heat molding when mixing the drug (Japanese Patent Publication No. Sho 50-17).
No. 525, JP-A-60-181029), and when used in combination with a bone morphogenetic factor, it cannot be used because of denaturation and deterioration due to heat.

Separately, using polylactic acid, polyglycolic acid, etc.
As a method of mixing a drug without performing heating and melting, a method of dissolving polylactic acid or the like using a solvent such as methylene chloride or chloroform and mixing the drug with it is known,
In this method as well, not only there is a problem of decomposition of the bone morphogenetic factor by the solvent, but also, since the base material after volatilization of the solvent becomes porous, the bone morphogenetic factor is almost released at the initial stage, and the sustained release is almost impossible. Will not be.

As described above, there are various problems with the osteogenic material, a material having biodegradability, a good affinity for an osteogenic factor, and an excellent osteogenic ability has not yet been found. It is.

(Problems to be Solved by the Invention) In order to solve the above problems, the present inventors have proposed a sustained release of a bone morphogenetic factor which is biodegradable, has a good affinity for a bone morphogenetic factor, and is suitable for bone formation. Intensive research has been conducted on a base material having a property and not having a foreign body reaction in a living body.

(Means for Solving the Problems) As a result, when a base obtained by reacting a polymer or copolymer of lactic acid and / or glycolic acid with polyethylene glycol is used as a support for an osteogenic factor, the above problem occurs. The applicant has filed an application (Japanese Patent Application No. 1-23052) for finding an excellent bone-forming biomaterial avoiding the above, but as a result of further study, such a support was further coated with lactic acid and / or glycolic acid. When a polymer or a copolymer is used in combination, the reason is not clear, but it has been found that bone formation is extremely excellent, and the present invention has been completed.

That is, the present invention provides a polymer or copolymer of the following compound (I) lactic acid and / or glycolic acid.

(II) a copolymer of a polymer or copolymer of lactic acid and / or glycolic acid (A) and polyethylene glycol (B), wherein the number average molecular weight of the component (A) is in the range of 400 to 5,000 And the number average molecular weight of component (B) is 150 to 200
Copolymer in the range of 0.

(III) Using osteogenic factors, (I), (II) and (III) were converted to (I) / (I
I) The present invention relates to a medical composition which is mixed in a weight ratio of 0.15 to 7.0.

(Operation) Hereinafter, the present invention will be described in more detail.

The present invention provides a polymer or copolymer of the following compound (I) lactic acid and / or glycolic acid.

(II) a copolymer of a polymer or copolymer of lactic acid and / or glycolic acid (A) and polyethylene glycol (B), wherein the number average molecular weight of the component (A) is in the range of 400 to 5,000 And the number average molecular weight of component (B) is 150 to 200
Copolymer in the range of 0.

(III) Using osteogenic factors, (I), (II) and (III) were converted to (I) / (I
I) It can be obtained by mixing in the range of 0.15 to 7.0 (weight ratio).

First, (I) a method for producing a polymer or copolymer of lactic acid and / or glycolic acid is well known. For example, lactic acid and glycolic acid are directly dehydrated under reduced pressure. By condensation, a polymer or copolymer can be obtained. (Yuhara et al., Engineering, 68 (5), 983 (1
965) Lactic acid and glycolic acid are distilled under reduced pressure in the presence of a catalyst such as zinc oxide to obtain lactide and glycolide, which are then polymerized in the presence of a catalyst such as tetraphenyltin and stannous chloride. It can also be manufactured by: (Kulk
arni, J. Biomed. Mater. Res., 5, 169 (1971)) The lactic acid monomer used in these cases is D
Any of a body, an L body, and a DL body may be used.

In the present invention, the number average molecular weight of the polymer or copolymer of lactic acid and / or glycolic acid thus obtained is 400 to 400.
Use 5,000 things.

In this case, if the molecular weight of these polymers deviates from this range and falls below 400, the lactic acid and glycolic acid monomers and oligomers are contained in a large amount, so that the acid value is high even after the reaction with polyethylene glycol described below. In addition, not only is the problem that the irritation to the living tissue is increased, but also it is not suitable as a base for controlling the release of bone morphogenetic factors.

Conversely, if the molecular weight exceeds 5,000, only those having a small effect of the present invention can be obtained.

Next, (II) a copolymer of lactic acid and / or glycolic acid polymer or copolymer (A) and polyethylene glycol (B), wherein the number average molecular weight of the component (A) is 400
5,000 and the number average molecular weight of component (B) is
The method for producing the copolymer in the range of 150 to 2000 will be described in detail.

The polymer or copolymer of lactic acid and / or glycolic acid used in the production of this copolymer is the same as that produced as described above.

A polyethylene glycol having a number average molecular weight in a range of approximately 150 to 2,000 is used as the polyethylene glycol to be subjected to the reaction.

The use ratio of the polymer or copolymer of lactic acid and / or glycolic acid and polyethylene glycol is such that the equivalent ratio of the latter to the former is in the range of 0.3 to 5.0.

In the case of a polymer or copolymer of lactic acid and / or glycolic acid, these equivalent ratios are based on the number of carboxyl groups (average) at the terminal of the polymer chain. Average).

In addition, when a polypropylene glycol or the like is used instead of the polyethylene glycol, an excellent medical composition as in the present invention cannot be obtained.

Concerning the method of carrying out the reaction using these raw materials, first, the polymer or copolymer of lactic acid and / or glycolic acid to be used is heated and melted at 100 to 250 ° C., which is their softening temperature, and polyethylene glycol is added thereto. Is added to carry out the reaction.

The reaction is carried out under the introduction of nitrogen gas, and the reaction time varies depending on the molecular weight of the lactic acid polymer or the like to be used and cannot be limited. However, the reaction requires about 1 to 20 hours.

As another method, it is also possible to use toluene, benzene or the like as a dehydrating agent at the time of heating and melting, or to carry out the reaction under reduced pressure of about 10 to 100 mmHg.

In the present invention, the (II) lactic acid and / or glycolic acid polymer or copolymer (A) and polyethylene glycol (B) thus obtained, wherein the number of the component (A) The copolymer having an average molecular weight in the range of 400 to 5,000 and a component (B) having a number average molecular weight in the range of 150 to 2,000 was added with (III) an osteogenic factor and mixed. I) A polymer or copolymer of lactic acid and / or glycolic acid is added and mixed.

Such a composition of the present invention gradually becomes better in sustained release effect as the mixing time elapses. The sustained release characteristics vary depending on the compositions and mixing ratios of the polymers and copolymers used, but usually reach equilibrium in about one week. Such a time-dependent change in the sustained release characteristics of the composition of the present invention is due to the fusion of the polymers (I) and (II), and the fusion causes the composition of the present invention to form an island structure. Incorporates osteogenic factors into it, and exerts a moderate sustained release effect.

In addition, an osteogenic factor is a substance that acts on undifferentiated mesenchymal cells extracellularly and has an action of inducing the hereditary trait to chondrocytes and osteoblasts (cartilage induction, bone induction), For example, BMP (Bone morphogenetic protein: Takaoka,
K., Biomedical Research, 2 (5) 466-471 (1981)). Separately, BDGF (Bone derived growth)
factor: Canalis, E., Science, 210, 1021 (1980)), CDF
(Cartilage derivth factor: Anderson, HC, Am.J.Path
ol, 44, 507 (1964)), SGF (Skeletal grown factor: F
arley, JR, Biochemistry, 21, 3508 (1982)), OGF (Os
teogenic factor: Amitani, K., Calcif.Tiss.Res., 17,139
(1975)).

Also, Kunio Takaoka et al., Orthopedic and Disaster Surgery, 26 (10), 1451
(1983) also discloses the extraction and purification method,
Any of these bone morphogenetic factors can be obtained by a known method.

In addition, human bones, bovine bones, or osteogenic factors obtained by genetic modification can also be used.

The copolymer of (I) a polymer or copolymer of lactic acid and / or glycolic acid used in the present invention and (II) a polymer or copolymer of lactic acid and / or glycolic acid (A) and polyethylene glycol (B) With respect to the proportion of the polymer (A) having a number average molecular weight in the range of 400 to 5,000 and the component (B) having a number average molecular weight in the range of 150 to 2,000, And (I) and (II) as (I) / (I
I) Use in the range of 0.15 to 7.0 (weight ratio).

That is, if the use ratio deviates from this range, the reason is not clear, but the osteogenicity is reduced, and an excellent medical composition as in the present invention cannot be obtained. In addition, when these compounds are mixed with an osteogenic factor, there is no need to heat the compound, and the osteogenic factor can be mixed at room temperature or at a low temperature equal to or lower than room temperature.

Regarding the amount of bone formation factors mixed,
Although not particularly limited by the bone defect volume, the composition of the raw material compounds, etc., it is preferably about 0.01% by weight or more based on the compounds (I) and (II).

That is, when the amount of the bone morphogenetic factor is 0.01% by weight or less, the amount of the bone morphogenetic factor eluted from the base is too small, and the bone morphogenetic factor is poorly eaten in vivo, and the bone formation is not sufficiently performed.

In addition, the medical composition of the present invention, besides the osteogenic factors, ceramics, metals and the like can also be used as aggregates, and antitumor agents, anticancer agents, anti-inflammatory agents or physiologically active substances can be mixed. It is possible.

Furthermore, a porous material such as hydroxyapatite as a bone component may be used in combination as a support when the biomaterial of the present invention is used.

(Effect of the Invention) As described above, the present invention provides a polymer or copolymer of the following compound (I) lactic acid and / or glycolic acid.

(II) a copolymer of a polymer or copolymer of lactic acid and / or glycolic acid (A) and polyethylene glycol (B), wherein the number average molecular weight of the component (A) is in the range of 400 to 5,000 And the number average molecular weight of component (B) is 150 to 200
Copolymer in the range of 0.

(III) It uses a bone morphogenetic factor and has the following excellent effects as a medical composition.

That is, since the components of the composition can be easily adjusted, the rate of bone formation and the rate of decomposition and absorption of the base material can be easily adjusted, and the material has excellent characteristics as a biomaterial. In addition, the base itself has excellent affinity with the living body, so that there is no foreign body reaction in the living body, and the bone forming ability by the bone forming factor is sufficiently exhibited.

(Examples) Examples of the present invention will be described below for further explanation, but the present invention is not limited thereto.

Example 1 90 g of polylactic acid (dl, number average molecular weight 650) and polyethylene glycol (number average molecular weight 190 to 210, Kishida Chemical Co., Ltd.) were placed in a 300 ml reactor equipped with a thermometer, a nitrogen inlet tube, and an exhaust port. (69 g) was immersed in an oil bath at 192 ° C.

5.5 while introducing nitrogen gas into the melt of the reactor.
A time reaction was performed.

After the reaction, the obtained liquid product was dispersed and dissolved in 600 ml of water, and then heated to 80 ° C to obtain a precipitated white polymer, which was dried at 70 ° C under reduced pressure.

The obtained lactic acid-polyethylene glycol copolymer (hereinafter abbreviated as PLEG) was subjected to ¹ H-NMR measurement. As a result, the unit content of polyethylene glycol was 41 mol%.

Separately, 50 g of 1-lactic acid (purity: 88%, manufactured by CCA) and 90 g of glycolic acid (reagent, manufactured by Kanto Chemical Co., Ltd.) were added to the same reactor as above, and the resultant was immersed in a 204 ° C. oil bath. ,
The polycondensation reaction was performed for 6.5 hours under the introduction of nitrogen gas.

The molecular weight of the obtained lactic acid-glycolic acid copolymer (hereinafter abbreviated as PLGA) was 1430, and as a result of composition analysis by ¹ H-NMR, the content of lactic acid was 22 mol%.

On the other hand, literature (TaKaoka, K et al, Biomedical Research,
2 (5), 466 (1981)), a bone morphogenetic factor (BMP) was obtained.

4 mg of this osteogenic factor and 60 mg of the above-mentioned PLEG were mixed at room temperature, and 32 mg of PLGA was added thereto and mixed.

This is filled into a cylinder molder, and the piston
Molding was performed under a pressure of 10 kg / cm ² to obtain a medical composition of the present invention.

This composition was sterilized using ethylene oxide gas, and then implanted under the back fascia of a mouse (8 weeks). At the same time as the transplantation, 10000 cpm of ⁸⁵ Sr was injected intraperitoneally into the mouse.

Three weeks later, the explant was taken out, and the uptake of ⁸⁵ Sr was examined by a γ-ray counter. The result was 3800 ± 470 cpm.

Further, as a result of examining the state of the bone tissue by soft X-ray, trabecular bone was observed at the formation site, and it was confirmed that bone formation was successfully performed.

Comparative Example 1 Atelocollagen (manufactured by Koken Co., Ltd.)
Was mixed with 400 mg of a 1% solution of

Further, 32 mg of powder of PLGA (1-lactic acid content 22 mol%, number average molecular weight 1430) manufactured in the same manner as in Example 1 and 4 mg of BMP powder were mixed, and the mixture was dried.

Further, 40 mg of PLEG used in Example 1 and 4 mg of BMP powder were mixed at room temperature and freeze-dried.

These were molded at a pressure of 100 kg / cm ² using a cylinder molding machine.

These were sterilized with ethylene oxide gas in the same manner as in Example 1, and then transplanted into mice. After 3 weeks, ⁸⁵ Sr was measured. As a result, 600 ± 70 cpm was used for atelocollagen, and only PLGA was used. Thing is 250 ± 30cpm, PL
Those using only EG had a value of 690 ± 80 cpm, and all of them had much less osteogenic properties than those of the present invention.

Example 2 Polylactic acid (dl, number average molecular weight 1,790) and polylactic acid (dl, number average molecular weight 1,030) produced in the same manner as in Example 1
The weight ratio of the polyethylene glycol (number average molecular weight: 380 to 420) copolymer (polyethylene glycol content by ¹ H-NMR: 39 mol%) was changed at the ratio shown in Table 1 and mixed with 2.5 mg of BMP powder. In the same manner as in Example 1, bone formation by mice was examined.

After the graft removed from the mouse 3 weeks, ⁸⁵
The uptake of Sr was measured and the results are shown in Table 1.

Claims (1)

(57) [Claims] 1. A polymer or copolymer of the following compound (I) lactic acid and / or glycolic acid. (II) a copolymer of a polymer or copolymer of lactic acid and / or glycolic acid (A) and polyethylene glycol (B), wherein the number average molecular weight of the component (A) is in the range of 400 to 5,000 And the number average molecular weight of component (B) is 150 to 200
Copolymer in the range of 0. (III) Using osteogenic factors, (I), (II) and (III) were converted to (I) / (I
I) A medical composition which is mixed in a weight ratio of 0.15 to 7.0.