JP2003093496A - Organic hard tissue-like hardened substance, powder composition and their use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an organic hard tissue-like hardened substance and a powder composition and preferable use for the organic hard tissue-like hardened substance and the powder composition capable of forming a part of an organic hard tissue, having a characteristic of not remaining in an organism by dissolving or decomposing in an organic tissue other than an organic hard tissue, and which can be suitably used not just as an alternate material of an organic hard tissue but also as a drug carrier or the like for a DDS. SOLUTION: The organic hard tissue-like hardened substance is provided by mixing a biopolymer and a calcium phosphate-based compound, obtaining the powder composition by conducting a mixture crushing process P3 of crushing the mixture, and hardening the powder composition by adding and kneading a hardening controlling agent in the powder composition.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a biohard tissue-like sclerosis capable of forming a substitute for biohard tissue and having biodegradability capable of being dissolved or decomposed in biomedical tissue other than biohard tissue. The present invention relates to a body and powder composition, and its use, and in particular, it can be used not only as a substitute material for biological hard tissue such as bone but also for a drug delivery system and a hard tissue-like hardened body. The present invention relates to a powder composition and its use.

[0002]

2. Description of the Related Art Calcium phosphate compounds have a composition similar to the inorganic components contained in living hard tissues such as teeth and bone tissues in the living body and exhibit biocompatibility. Therefore, it can be suitably used as a biomaterial such as an artificial tooth or an artificial bone as known in many conventionally known techniques.

The calcium phosphate-based compound can also be used in a drug delivery system (hereinafter abbreviated as DDS). Specifically, by introducing a carrier in which a drug is carried by a calcium phosphate compound into the vicinity of the affected part in the living body, the drug is released from the carrier and the drug is supplied to the affected part in the living body.

[0004] In the conventionally known general technique of the DDS, a carrier shaped into a predetermined shape is embedded in a hard tissue of a living body, and the drug is released from the embedded carrier. That is, in the general DDS technique, a molded product that has been molded in advance by compression molding or the like is introduced into a living body as a carrier.

Therefore, in such a known technique, it is necessary to process the above-mentioned molded product in a living body into a shape conforming to the embedding site, which complicates the method of use. Also, DD
In the application to S, for example, a protein may be used as a drug, but in this case, the protein drug is easily deactivated during molding. Therefore, a wide variety of drugs cannot be used in the above-mentioned known technique. Furthermore, a surgical operation is required to introduce the molded product into the living body,
It is a burden on both the doctor who uses the drug and the patient who receives the drug.

Therefore, in order to address the above problems,
Japanese Unexamined Patent Publication No. 6-228011 proposes a calcium phosphate-based drug sustained-release body in which a drug is blended with a calcium phosphate-based compound and the calcium phosphate-based compound is self-cured. This calcium phosphate-based drug sustained-release body introduces a slurry-like or clay-like composition into a living body and self-hardens. As a result, it is not necessary to process the molded product into a shape conforming to the embedding site, and inactivation of the drug hardly occurs during molding, so a wide variety of drugs can be used. In addition, since the slurry-like or clay-like composition can be introduced into a living body by a syringe, surgical operation becomes unnecessary, and the burden on both the doctor and the patient can be reduced.

[0007]

However, in the above-mentioned conventional techniques, although a composition containing a calcium phosphate compound can be used as a sustained-release drug, the use of the composition is limited to some extent due to the characteristics of the composition. It has a problem of lacking versatility.

The sustained-release form of the drug in the above publication focuses on the compatibility with living hard tissues such as bone tissues, so that when it is introduced into living tissues other than living hard tissues, it remains without being sufficiently biodegraded. There is a risk that That is, since the drug sustained-release body is relatively stably maintained in the body as an artificial biological hard tissue, it is likely to remain in the body even after releasing the drug and losing its function as the drug sustained-release body. . This drug sustained-release body can form a part of the biological hard tissue if it is formed in the biological hard tissue, but if it is formed in other biological tissues, the site that should not originally exist. This is not preferable because it results in a state in which a living hard tissue exists.
Therefore, the technique of the above publication is practically applicable only to the hard tissue of the living body and lacks versatility.

The present invention has been made to solve the above-mentioned conventional problems, and an object thereof is to form a part of a living hard tissue and to use the living tissue other than the living hard tissue. , Which has the property of being dissolved or decomposed to avoid its residue in the living body, and can be suitably used not only as an alternative material for living hard tissue but also as a drug carrier for DDS and the like. And a powder composition,
And a preferred use of this hard tissue-like cured body and powder composition.

[0010]

Means for Solving the Problems As a result of intensive investigations by the present inventors in view of the above problems, as a result of a hard tissue-like cured body containing a biopolymer and a calcium phosphate compound, By mixing with a calcium-containing compound of a hardening composition and hardening, it is possible to improve the biodegradability of the obtained hard tissue-like hardened body, and further to control the biodegradability and release of the loaded drug. Heading out, the present invention has been completed.

[0011] That is, in order to solve the above-mentioned problems, the hard tissue-like hardened body of the present invention is a hard body like hard tissue containing a biopolymer and a calcium phosphate compound. And a calcium-containing compound having a self-hardening composition are mixed and cured.

According to the above constitution, the biopolymer and the calcium-containing compound having a self-hardening composition are mixed and hardened. Therefore, high biostability, biocompatibility, and high biodegradability can be exhibited. In addition, by controlling the mixed state or dispersed state of each of these components, an alternative material for living hard tissue or DDS
It can be suitably used as a drug carrier for use.

Further, the powder composition of the present invention is a powder composition before the above-mentioned hard tissue-like hardened body is hardened, and the powder composition contains phosphoric acid or phosphate as a main component and water. The above-mentioned hard tissue-like cured product is obtained by adding and kneading a hardening control agent containing as a main solvent or water.

According to the above-mentioned constitution, the curing can be further promoted by the addition of the curing control agent or water, so that it can be suitably used as a substitute material for a living body hard tissue or a drug carrier for DDS. It is possible to easily and surely obtain a high quality living body hard tissue-like cured body.

In the above powder composition, the biopolymer is preferably a fibrous polymer contained in the connective tissue of a living body or a modified form thereof, and the fibrous polymer is composed of collagen and hyaluronic acid. More preferably, it is at least one.

In the powder composition, the calcium-containing compound may be calcium hydrogen phosphate, calcium hydrogen phosphate or its dihydrate, α-tricalcium phosphate, tetracalcium phosphate, and phosphoric acid. It is preferably at least one of octacalcium. The calcium-containing compound is preferably at least one of calcium-containing glass powder and calcium-containing glass crystallization powder.

In the above powder composition, it is preferable that the calcium-containing compound contained in the powder composition finally becomes hydroxyapatite after curing.

Further, when the weight of the biopolymer is 1, the mixing ratio of the calcium-containing compound to the biopolymer is preferably in the range of 0.1 to 10 by weight.

According to each of the above-mentioned constitutions, it is possible to realize a component composition closer to that of a living hard tissue, and therefore the characteristics of the powder composition according to the present invention (biostability and biocompatibility,
Biodegradability) can be further improved.

The above powder composition preferably further contains a drug in addition to the biopolymer and the calcium-containing compound.

According to the above-mentioned constitution, the powder composition according to the present invention can be preferably used in the drug delivery system by using, for example, various therapeutic agents as the drug. If a stimulating substance that controls the growth of living hard tissue is used as the drug, the powder composition according to the present invention can be preferably used as a substitute for living hard tissue such as artificial bone.

In addition, the hard tissue-like hardened body according to the present invention comprises, in addition to the powder composition of each of the above constitutions, a hardening control agent containing phosphoric acid or a phosphate as a main component and water as a main solvent, or water. It is characterized by being kneaded, kneaded, and cured.

According to the above-mentioned constitution, the curing can be further promoted by the addition of the curing control agent or water, so that it can be suitably used as a substitute material for a living hard tissue or a drug carrier for DDS. It is possible to easily and surely obtain a high quality living body hard tissue-like cured body.

The powder composition and the hard tissue-like hardened body according to the present invention can be used, for example, for treating the functional disorders of various living bodies by using the powdered composition or hardened body like the hard tissue described above. A drug carrier carrying a therapeutic agent, a powder composition or a living hard tissue-like cured material having the above-mentioned constitutions, and a living hard tissue-like substitute material containing a stimulating substance for controlling the growth of living hard tissue Can be mentioned.

According to the above-mentioned constitution, by appropriately adding or supporting a drug to the above powder composition, it is possible to obtain a hard tissue-like cured body of living body according to the use, so that the versatility of the present invention is enhanced. be able to.

Therefore, as a more specific method of using the present invention, a hard tissue-like hardened body forming set containing the above powder composition and a hardening control agent or water can be mentioned.

At this time, the powder composition, the curing control agent,
Water has been subjected to aseptic processing. Further, the hard tissue-like hardened body forming set, a syringe for injecting a fluid or deformable kneaded product obtained by kneading the powder composition with a hardening control agent or water, and a predetermined amount The drug may or may not be contained. When various drugs are included in the hard tissue-like cured body forming set, the crushing time and the like can be adjusted in advance according to the type of the drug. On the other hand, when various drugs are not included in the hard tissue-like cured body forming set, it is possible to appropriately select and use various drugs according to the treatment. The versatility of the forming set can be improved.

[0028]

BEST MODE FOR CARRYING OUT THE INVENTION An embodiment of the present invention will be described below with reference to FIGS. The present invention is not limited to this.

The hard tissue-like hardened body of the present invention (hereinafter abbreviated as hardened body) and the method for producing the same are obtained by mixing a biopolymer and a calcium phosphate compound, pulverizing and hardening the mixture. It is a thing. In the present invention, the biopolymer and the calcium phosphate compound are mixed and pulverized to self-cure the mixture. As a result, a cured product having excellent properties can be easily and reliably obtained.

Specifically, the cured product according to the present invention can be manufactured, for example, by the manufacturing method of 5 steps shown in FIG. In addition, P1 to P5 in FIG. 1 indicate the respective steps.

First, calcium phosphate compounds and biopolymers are used as raw materials. This calcium phosphate-based compound is pulverized by a vibration mill, a ball mill, or the like in the pulverizing step before mixing P1. This pre-mixing pulverizing step may not be performed depending on the characteristics of the cured product.

Next, in the P2 mixing step, the calcium phosphate compound and the biopolymer are mixed to obtain a mixture.
The mixing method is not particularly limited. And P
In the mixture pulverizing step of 3, the mixture is pulverized again by a vibration mill or a ball mill. As a result, a powder composition containing the biopolymer and the calcium phosphate compound is obtained.

To this powder composition, a phosphoric acid-based aqueous solution containing phosphoric acid or a phosphate as a main component is added in the step of adding a curing control agent of P4, and in the kneading step of P5, the powder composition and phosphoric acid are added. Knead with the system aqueous solution. Through this kneading process, the powder composition is in the form of slurry or clay (dough)
The resulting kneaded product will self-cure after a lapse of a predetermined time.
Therefore, the standing for this predetermined time is a curing step of curing the mixture (powder composition) of the biopolymer and the calcium phosphate compound. Furthermore, the powder composition, after curing,
Transfers to a hardened body.

Although not shown, if necessary, the kneaded product may be poured into a mold and molded to produce a cured product. That is, in the method for producing a cured product according to the present invention,
Further, a molding step may be included.

By performing the P3 mixture pulverizing step before the curing step, the biopolymer and the calcium phosphate compound are mixed, pulverized and then cured. Therefore, since the particle size of each of these components can be adjusted by pulverization, it becomes possible to control the mixed state or dispersed state of these respective components. As a result, it is possible to easily and surely obtain a high-quality cured body that can be suitably used as a substitute material for living body hard tissue or a drug carrier for a drug delivery system (DDS).

The pulverizing conditions in the P3 mixture pulverizing step are not particularly limited, but among these pulverizing conditions, the pulverizing time is preferably changed appropriately according to the use of the cured product.

As will be described later, the hardened material according to the present invention can be suitably used as a biohard tissue substitute material or a drug carrier for DDS, but the crushing time can be appropriately changed according to the application. The particle size of the biopolymer and the calcium phosphate-based compound can be adjusted. As a result, it becomes possible to control the mixed state or dispersed state of each of these components and the voids in the cured product, and it is possible to control the properties of the obtained cured product.

The specific range of the crushing time is not particularly limited, but is usually about 1 minute to 24 hours. The change in the crushing time will be specifically described below.

In the process of pulverizing the mixture of P3, for example,
As shown in the diagram on the left side of FIG. 2, if a mixture of two types of calcium phosphate-based compound particles 1a and 1b and biopolymer 2 is pulverized, the resulting powder composition will be calcium phosphate-based compound particles 1a and 1b. The biopolymer 2 and the biopolymer 2 are evenly mixed with each other in size to form a fine matrix. Therefore, in the curing step, the calcium phosphate-based compound particles 1a and 1b in the powder composition are
In theory, everything can be transferred. Therefore, as shown in the diagram on the right side of FIG. 2, the transition substance 10 of the calcium phosphate-based compound particles 1a and 1b has a crystal structure in which the biopolymer 2 is uniformly distributed, and A cured product having a structure in which the biopolymer 2 is incorporated can be obtained.

The cured product has a crystal structure and a composition similar to those of living hard tissues, and can be used as a biomaterial for living hard tissues such as bones, teeth, joints and cartilage. By providing the mixture pulverizing step of P3, the compressive strength of the hardened body is also increased, and thus it can be suitably used as a biomaterial for a living hard tissue.

On the other hand, in the mixture which has not been pulverized, as shown in the diagram on the left side of FIG. 3, the two types of calcium phosphate compound particles 1a and 1b and the biopolymer 2 are not uniform in size but uniform. It is distributed in. Therefore, it is possible to obtain a cured product in which all the calcium phosphate-based compound particles 1a and 1b cannot be transferred, and the biopolymer 2 and the transfer product 10 are not uniformly mixed. In other words, the crystal structure of the cured product is, as shown in the diagram on the right side of FIG. 3, two types of calcium phosphate-based compound particles 1 before transition.
The a.1b remains, and the biopolymer 2 has a nonuniform distribution in which it is locally hardened.

Therefore, in the present invention, the crystal structure of the transition product 10 of the calcium phosphate compound particles 1a and 1b is controlled by appropriately changing the grinding time, and further, the size of the voids of the transition product 10 is controlled. Can be controlled. That is, if the pulverization time is extended, the crystal structure and voids of the transition product 10 are made uniform and fine (FIG. 2). Further, if the crushing time is shortened, the crystal structure and voids of the transition product 10 can be intentionally made nonuniform (FIG. 3). As a result, by appropriately changing the crushing time, the mixed state or dispersed state of the biopolymer 2 and the calcium phosphate compound particles 1a and 1b is controlled, and further, the size and the size of the voids of the transition material 10 are introduced. It is possible to control the amount of the biopolymer 2, and it is possible to control the properties of the obtained cured product.

Since other crushing conditions depend on a crushing device such as a vibration mill or a ball mill, it may be appropriately set according to the characteristics of each crushing device. The crusher is
The present invention is not limited to the vibration mill and the ball mill, and may be a pin mill, a hammer mill, a jet mill, or the like, and may be appropriately selected so as to obtain a desired particle size.

The biopolymer used in the cured product according to the present invention is not particularly limited, but examples thereof include fibrous proteins such as collagen and gelatin or modified products thereof; hyaluronic acid, chondroitin sulfate, dermatan. Glycosaminoglycans (mucopolysaccharides) such as sulfuric acid, heparan sulfate, heparin, and keratan sulfate; other polysaccharides such as chitin and chitosan; and the like. Among them, it is preferable to be a fibrous polymer contained in the connective tissue of a living body such as fibrous protein or glycosaminoglycan or a modified form thereof, and this fibrous polymer is at least one of collagen and hyaluronic acid. Is more preferable.

The fibrous polymer in the present embodiment refers to a polymer compound contained in the collagen fiber / reticulated fiber / elastic fiber contained in the connective tissue.

In the cured product according to the present invention, synthetic polymers may be used in addition to biopolymers as long as they do not affect the living body. The synthetic polymer is not particularly limited as long as it has high biocompatibility, and examples thereof include polylactic acid, polyvinyl alcohol, and polyacrylic acid.

The calcium phosphate compound used in the cured product according to the present invention is not particularly limited, but examples thereof include calcium hydrogen phosphate (DCPD, chemical formula: CaHPO ₄ ), calcium hydrogen phosphate. dihydrate _{(CaHPO 4 · 2H 2 O)} , α
-Tricalcium phosphate (TCP, chemical formula: Ca ₃ (PO
₄ ) ₂ ), tetracalcium phosphate (TTCP, chemical formula: C
a ₄ (PO ₄ ) ₂ ) and octacalcium phosphate (Ca
₈ H ₂ (PO ₄ ) ₆ (OH) ₂ ) and other simple calcium phosphates; hydroxyapatite (Ca ₁₀ (PO ₄ ) ₅
(OH) ₂ ) and carbonate apatite (Ca ₁₀ (PO ₄ ))
₅ (CO ₃ )) and the like. Each of these compounds may be used alone or in combination of two or more.

The calcium phosphate compound is preferably used so that the Ca / P ratio is 1.0 to 2.0. Thereby, more excellent biostability and biocompatibility can be provided, and self-curing can be more suitably performed.

Instead of the above-mentioned calcium phosphate compound, a precursor of a calcium phosphate compound which becomes a calcium phosphate compound by mixing and kneading a phosphoric acid aqueous solution containing phosphoric acid or a phosphate may be used.

The precursor of the calcium phosphate compound is not particularly limited, but examples thereof include calcium-containing glass powder and calcium-containing glass crystallization powder. Here, the glass crystallization powder means a powder of a compound crystallized from glass. Only one of these precursors may be used, or 2
You may use more than one kind.

In the calcium-containing glass powder and the calcium-containing glass crystallized powder, it is more preferable to use one having a Ca content in the range of 30% by weight to 70% by weight. Particularly preferable composition ranges of the calcium-containing glass powder and the calcium-containing glass crystallized powder include CaO of 30 to 70% by weight, SiO ₂ of 30 to 70% by weight, P ₂ O ₅ of 0 to 60% by weight, and CaF.
₂ is 0 to 5% by weight, MgO is 0 to 20% by weight, Na ₂ O
Is preferably 0 to 20% by weight.

When CaO is less than 30% by weight,
When the chemical bondability with bone is lowered and the content is more than 70% by weight, the phenomenon that the glass becomes cloudy due to the fine crystals that precipitate when the glass transforms into crystals, that is, the devitrification becomes strong and vitrification occurs Becomes difficult. When the content of SiO ₂ is less than 30% by weight or more than 70% by weight, the devitrification becomes strong and vitrification becomes difficult. If the content of P ₂ O ₅ is more than 60% by weight, the meltability of the glass is increased, the chemical durability is lowered, and the glass is easily eroded. CaF
_{When the} content of ₂ is more than 5% by weight, the devitrification becomes strong and vitrification becomes difficult. MgO and Na ₂ O are 2 each
When it is more than 0% by weight, the melting property of the glass is too high, the strength of the glass is lowered, and the chemical bondability with the living body hard tissue is lowered.

As described above, the cured product according to the present invention only needs to finally contain the biopolymer and the calcium phosphate compound, and the compound mixed with the biopolymer in the manufacturing process and pulverized is the calcium phosphate compound. It may be a compound or a precursor thereof. In the present embodiment, the calcium phosphate-based compound and its precursor are collectively referred to as a calcium-containing compound.

In order for the cured product of the present invention to exhibit excellent biostability and biocompatibility, the molar ratio Ca / P _{mol of} calcium and phosphorus (phosphate group) is 1.0 to 2.0.
Is preferably within the range (1.0 ≦ Ca / P _mol
≦ 2.0). Therefore, in the mixing step of P2, when the weight of the biopolymer is 1, the mixing ratio of the calcium-containing compound to the biopolymer is 0.1 or more and 10 by weight.
It is preferably within the following range, and more preferably about 4. That is, the mixing ratio of the biopolymer and the calcium-containing compound is preferably within the range of 1:10 to 10: 1 by weight, and preferably 2: 8. By setting the mixing ratio, it is possible to obtain a hardened body having a bone component ratio similar to that in the living body.

Further, in the cured product according to the present invention,
It is more preferable that the calcium-containing compound finally becomes hydroxyapatite after curing. As is well known, hydroxyapatite has excellent biocompatibility and is present as a main component of living hard tissues such as bones, teeth, joints, and cartilage, so it is used as an alternative material for artificial bones and teeth. It's very suitable. Therefore, it is preferable that the cured product of the present invention also contains hydroxyapatite as the calcium phosphate compound.

The hydroxyapatite is prepared by using tetracalcium phosphate in the above simple calcium phosphates and calcium hydrogen phosphate or its dihydrate so that Ca / P _mol is 1.67. If it does, it will be generated by these transitions in the curing step. Therefore, in the production method according to the present invention, when it is desired to obtain a cured product containing hydroxyapatite, the calcium-containing compound used as a raw material may be compounded as described above.

The phosphoric acid-based aqueous solution functions as a curing control agent that accelerates the curing of the calcium-containing compound. Therefore, by performing the above-mentioned P4 curing control agent adding step and P5 kneading step, It is possible to improve the production efficiency of the cured product.

Specifically, the phosphoric acid-based aqueous solution is an aqueous solution containing phosphoric acid or a phosphate as a main component, and includes diammonium hydrogen phosphate, ammonium dihydrogen phosphate, disodium hydrogen phosphate and phosphorus. It is obtained by dissolving sodium dihydrogen acid or the like in water. The calcium phosphate-based compound is strongly acidic, but the pH is adjusted to 7.0 to 7.4 by adding and kneading the phosphoric acid-based aqueous solution, so that it is less irritating to the living body. Also, Ca-containing glass powder or C
When a phosphoric acid-based aqueous solution is used as the a-containing glass crystallization powder, an inflammatory reaction with respect to a biological tissue is not caused if a substantially neutral solution having a pH of about 6.0 to 8.5 is used. This phosphoric acid-based aqueous solution may contain a compound other than phosphoric acid or a phosphate, and may contain a solvent other than water, as long as it does not adversely affect the living body.

When such a phosphoric acid-based aqueous solution is used as a curing control agent, when the calcium-containing compound is a calcium phosphate-based compound, the curing can be further promoted by adding the phosphoric acid-based aqueous solution. On the other hand, if the calcium-containing compound is a precursor of a calcium phosphate-based compound, the calcium phosphate-based compound can be generated by the addition of a phosphoric acid-based aqueous solution and can be cured early, so that the curing step can be controlled more efficiently. be able to.

When the calcium phosphate-based compound is used as the calcium-containing compound from the beginning, the phosphoric acid-based aqueous solution is not necessarily used as the curing control agent.
Due to the presence of water, it self-hardens and transforms. Therefore, depending on the application, it is possible to obtain a cured product only by carrying out P1 to P3, without carrying out the hardening control agent adding step of P4 and the kneading step of P5. However, in order to control the curing more efficiently, P4.
It is preferred to carry out P5.

When P4 and P5 are carried out, the powder composition is kneaded with a phosphoric acid-based aqueous solution to form a slurry-like or clay-like (dough-like) kneaded product, and then, in particular, molding such as compression molding is performed. It self-cure without any steps. That is, in the stage before self-curing, the kneaded product has fluidity or deformability, so that a cured product having a free shape can be easily obtained. Moreover, since the above-mentioned self-curing can be realized under temperature conditions near body temperature or room temperature,
Since the cured product having a desired shape can be obtained only by administering the kneaded product into the living body, the handling becomes easy.

Further, if it is in a slurry or clay state, it can be injected into the living body by a syringe. When introduced into the living body in the form of a slurry or clay, the calcium-containing compound will self-cure and transfer under the in-vivo environment. Therefore, the surgical operation required when introducing the cured product into the living body can be minimized.

The cured product of the present invention is attacked by osteoclasts when introduced into living tissues other than hard tissues. Osteoclasts are closely related to bone resorption and have a function of dissolving bone. The reason for being attacked by osteoclasts is that the hardened body contains a biopolymer and thus has a composition more similar to that of a living hard tissue.
That is, the hardened body in the living tissue contains not only the calcium-containing compound but also the biopolymer, so that it is recognized as living hard tissue by the osteoclasts and is eroded. The rate of erosion by osteoclasts can be controlled by controlling the biopolymer content in the cured product and the crushing time in the P3 mixture crushing step, so the biodegradation rate of the cured product in vivo Can be controlled.

Furthermore, the cured product of the present invention will be described later in DDS.
When it is used as a drug carrier of, it is attacked by osteoclasts. That is, the drug carrier of the present invention can release the drug even by erosion of osteoclasts in the living body. The drug release by osteoclasts has not been previously proposed, but is newly discovered in the present invention.

The hardened body eroded by osteoclasts is decomposed into biopolymer and calcium-containing compound. Since these biopolymers and calcium-containing compounds are not only components in the living body but also soluble in body fluids,
It is not adversely affected even if it is taken into the living body. Calcium-containing compounds may also aid in the formation of biological hard tissue. Further, since the cured product according to the present invention is excellent in biocompatibility, when it is embedded or filled in a living body hard tissue, it is taken in as a part of the living body hard tissue or is absorbed and is used as an artificial living body hard tissue. It can also play a role.

As described above, the cured product according to the present invention is
Calcium-containing compounds that are very similar to the inorganic components that make up hard tissues such as bones, teeth, joints, and cartilage in the living body, and fibers such as collagen and hyaluronic acid that are also widely distributed in connective tissues of the living body. It contains a polymer.
Therefore, it has biostability that can exist stably in a living body for a long time, and biocompatibility that can coexist in a living body without giving a bad stimulus or strong irritation to the living body. It is a particularly excellent alternative material.

The characteristics of the cured product according to the present invention can be controlled by defining the above conditions. In particular, by appropriately selecting each of the above conditions, it becomes possible to realize a component composition that is closer to that of a biological hard tissue. Therefore, the properties such as biostability, biocompatibility, and biodegradability of the cured product according to the present invention can be further improved.

The cured product according to the present invention preferably further contains a drug in addition to the biopolymer and the calcium-containing compound. For example, by using various therapeutic agents as drugs, the cured product according to the present invention can be DD
It can be suitably used as a drug carrier of S. If, for example, a stimulating substance that controls the growth of biological hard tissue is used as the drug, the cured product according to the present invention can be preferably used as a material for replacing biological hard tissue such as artificial bone.

Specifically, when used as a drug carrier for DDS, the drug may be an antibacterial agent, an anticancer agent, an antitumor agent, an antiinflammatory agent, an antibiotic, a diabetic preparation, a living hard tissue growth stimulating hormone, etc. The medical drug, nutritional supplement such as nutritional supplement, etc. can be used, but the present invention is not limited thereto. Also, these drugs may be only one kind, and
It may be more than one kind.

In the DDS of the present invention, the drug carrier, after being introduced into living tissue, releases the drug by diffusion from the voids of the drug carrier, and at the same time, as described above, It also releases the drug by erosion.

On the other hand, conventionally, the drug was released by allowing the drug to be supported on a cured product containing no biopolymer and diffusing the drug from the voids of the cured product.

However, since the drug carrier of the present invention contains the biopolymer, it has a structure in which the biopolymer enters the voids formed by the transfer of the calcium-containing compound. Therefore, the release of the drug by diffusion from the drug carrier is suppressed by blocking the voids by the biopolymer, or accelerated by increasing the porosity due to the presence of the biopolymer. That is, the drug release rate of the drug carrier can be controlled by adjusting the type and amount of biopolymer contained in the drug carrier and the molecular weight of the drug. For example, when the drug carrier has small voids and the molecular weight of the drug carried is large, it becomes possible to retain the drug inside the drug carrier for a long time, which allows the drug to be released over a long period of time. it can.

Further, since the drug carrier contains a biopolymer, the drug diffusion may be suppressed in some cases.
In such a case, the drug carrier can retain the drug until it decomposes and disappears due to the erosion of osteoclasts, and the drug effect can be maintained for a long time.

Further, since the drug carrier described above is manufactured by utilizing the self-hardening property of the calcium-containing compound, it can be used for a very wide variety of drugs. For example, when a proteinaceous drug is used as the drug, firing or compression molding to cure the calcium-containing compound causes deactivation of the drug. On the other hand, the self-hardening of the calcium-containing compound is achieved at body temperature or around room temperature, so that the drug is not inactivated.

As an example of the above-mentioned drug carrier, the addition of a drug which becomes a biohard tissue formation stimulating factor can induce the formation of biohard tissue. That is, by introducing this drug carrier into a living body, the amount of bone mineral (BMC), which represents the amount of calcium in the living body, increases, and as a result, the formation of living body hard tissue is promoted. Such a drug carrier can be used as a bio-hard tissue substitute material as described above.

The increase in BMC is observed in vivo when a mixture of a biopolymer and a calcium phosphate compound is pulverized and a substance which acts as a biohard tissue formation stimulating factor is added. A drug carrier that does not contain a substance that becomes a biopolymer or a biohard tissue stimulating factor, or a drug carrier that has not been pulverized with a mixture of a biopolymer and a calcium phosphate-based compound, is introduced into a living body. , BMC decreases slowly, but BMC does not increase.

In the method for producing the drug carrier described above, in the method for producing the cured product shown in FIG. 1, only the drug needs to be added before the curing step. Preferably, a method of adding a drug during the steps of P3 to P5 and kneading with the biopolymer and the calcium-containing compound is good.

In the present invention, the above-mentioned powder composition itself has a sufficient utility value. That is, by appropriately adding or supporting a drug to the powder composition, it is possible to obtain a cured product depending on the application, so that the versatility of the present invention can be enhanced.

Specifically, for example, a composition obtained by aseptically treating the above powder composition and a composition obtained by aseptically treating the above-mentioned curing control agent or sterile water may be combined to form a cured product forming set. As a result, a cured product can be appropriately formed in the living body during treatment, so that the utility value of the present invention can be further improved.

At this time, a slurry-like or clay-like (dough-like) kneaded product obtained by kneading the above-mentioned powder composition and the curing control agent or sterile water is injected into the living body into the above-mentioned cured body forming set. A syringe to be used and a predetermined drug may be contained. When various drugs are contained in the cured product forming set, the crushing time and the like can be adjusted in advance according to the type of the drug. On the other hand, when various drugs are not contained in the cured product forming set, various drugs can be appropriately selected and used according to the treatment, thus improving the versatility of the cured product forming set according to the present invention. be able to.

[0081]

EXAMPLES The present invention will be described in more detail based on Examples and Comparative Examples and FIGS. 4 to 20, but the present invention is not limited to these.

In each of the following Examples and Comparative Examples, the compression strength of the cured product was measured, the X-ray diffraction result of the cured product powder was evaluated, the surface condition of the cured product was evaluated, and the calcium distribution of the cured product was evaluated. The composition of the cured product, bone density, and in vitro drug elution were evaluated or measured by the following methods.

[Measurement of Compressive Strength of Cured Body] Using a material testing machine (AUTOGRAPH IS-1500, manufactured by Shimadzu Corp.), compression of the obtained columnar cured body was performed at a compression rate of 1.5 mm / min. The strength was measured.

[Evaluation of X-ray Diffraction Result of Powder] The obtained cured product was crushed in an agate mortar to give a powder, and this powder was analyzed by powder X-ray diffraction to evaluate the similarity to the hard tissue of the living body. . Specifically, first, a powder X-ray diffractometer (XD610, manufactured by Shimadzu Corporation) was used to prepare X-ray powder from rat femur in advance.
The diffraction peak of the line diffraction was measured, and then the diffraction peak of the X-ray diffraction was measured from the powder of the target cured product. Then, the patterns of the respective diffraction peaks were compared, and when the diffraction peaks of both were substantially coincident with each other, ◯ was evaluated, when they were close to each other, Δ was evaluated, and when they were hardly coincident with each other, x was evaluated.

[Evaluation of Surface Condition of Cured Product] The surface condition of the obtained columnar cured product was examined with a scanning electron microscope (JSM5600L).
V, manufactured by JEOL Ltd.) and observed at a magnification of 2000 times.
Similarly, the surface condition of bovine bone was also observed, and the surface condition was evaluated by visually comparing these observation results. The case where the surface states are very similar to each other was evaluated as ◯, and the case where they were not similar was evaluated as x.

[Evaluation of Calcium Distribution of Cured Product] The calcium distribution of the obtained cylindrical cured product was measured by an energy dispersive X-ray spectroscope (JED2200, manufactured by JEOL Ltd.). In addition, the calcium distribution was similarly measured for bovine bone. Then, the results of the calcium distributions were compared with each other, and when the states of the calcium distributions were very similar to each other, it was evaluated as ◯, and when they were not similar, evaluated as x.

[Evaluation of Composition of Cured Product] The obtained cylindrical cured product was subjected to elemental analysis by the above-mentioned energy dispersive X-ray spectroscopy. In addition, elemental analysis was similarly performed on bovine bone. Then, the results of these elemental analyzes were compared, and when the results of each elemental analysis were very similar to each other, it was evaluated as ◯, and when they were not similar, it was evaluated as x.

[Measurement of Bone Density] Cement as a hardened body subcutaneously administered to a living body of a rat was measured by a dual energy X-ray absorption method using a bone density measuring device (DSC-600R, manufactured by ALOKA). The bone mineral content (BMC) of the cement was measured and evaluated as the bone density of the cement. For comparison, the bone density around the vertebral bones on the back of the rat was also measured with the above bone density measuring device.

[Measurement of In Vitro Drug Elution] A drug carrier carrying indomethacin (IMC) was immersed in 25 mL of the simulated body fluid SBF (pH 7.4), and the dissolution tester (THERMO
STATIC SHAKING BATH TRH-S100, manufactured by Thomas Kagaku Co., Ltd.) was used and shaken at 37 ° C. and 90 rpm / min.
Then, the total amount of SBF is exchanged over time, and the concentration of IMC in the SBF is measured.
The amount of IMC eluted from the drug carrier in vitro was measured. The concentration of IMC in SBF was measured using a visible ultraviolet spectrophotometer (UV160 type, manufactured by Shimadzu Corporation).
It was determined from the absorbance at a wavelength of 54 nm.

Example 1 Calcium hydrogen phosphate (DC
PD) and tetracalcium phosphate (TTCP) were mixed at a molar ratio of 1: 1 and pulverized for 10 minutes at 90 rpm / min using a centrifugal ball mill (manufactured by Rita Mitamura) (P1). (Pulverization step before mixing). Next, 5 parts by weight of collagen was added to 100 parts by weight of this mixture (P2 mixing step), and the mixture was pulverized for 5 minutes under the same conditions using the above vibration mill (P3 mixture pulverization step). An APC5G5 composition was obtained as a powder composition according to the invention.

Next, 500 m of this APC5G5 composition was added.
g, add 0.2 mL of 11 mM phosphoric acid aqueous solution (P
(4) step of adding a curing control agent) and kneaded well on a glass plate using a spatula (kneading step of P5). The obtained kneaded product was filled in a plastic cylinder having a diameter of 6 mm and a height of 12 mm, and while being pressurized, it was left to stand in a constant temperature bath at 37 ° C. and 100% relative humidity for 24 hours to be cured (curing step). Then, it was dried under reduced pressure for 24 hours to obtain a solid APC5G5 solid body having a diameter of 6 mm and a height of 12 mm as a hard body-like hardened body according to the present invention. The compressive strength of this APC5G5 solid was measured by the method described above. The results are shown in FIG. 4 and Table 1.

Example 2 An APC5G20 composition was obtained as a powder composition in the same manner as in Example 1 except that the pulverization time in the P3 mixture pulverizing step was 20 minutes. APC as a tissue-like cured material
A 5G20 solid was obtained. The compressive strength of this APC5G20 solid was measured by the method described above. The results are shown in FIG. 4 and Table 1.

The APC5G20 solid was pulverized by the above-mentioned method to obtain APC5G20 powder.
The X-ray diffraction results of the G20 powder were evaluated by the method described above.
The results are shown in FIG. 5 (e) and Table 2.

Comparative Example 1 A comparative powder composition was prepared in the same manner as in Example 1 except that the pulverizing time in the P3 mixture pulverizing step was 0 minute, that is, the P3 mixture pulverizing step was not performed. APC5 composition as a cured product was obtained, and further APC5 solid as a comparative cured product was obtained.
The compressive strength of this APC5 solid was evaluated by the method described above. The results are shown in FIG. 4 and Table 1.

Also, in the same manner as in Example 2, APC5 powder was obtained from the APC5 solid, and the X-ray diffraction result of this APC5 powder was evaluated by the method described above. The result is shown in FIG.
And shown in Table 2.

[Example 3] A as a powder composition according to the present invention was prepared in the same manner as in Example 1 except that the amount of collagen added in the mixing step of P2 was 20 parts by weight.
A PC20G5 composition was obtained, and an APC20G5 solid as a hard tissue-like cured body was obtained. The compressive strength of this APC20G5 solid was measured by the method described above. The results are shown in FIG. 4 and Table 1.

[Example 4] APC2 as a powder composition according to the present invention was prepared in the same manner as in Example 3 except that the pulverizing time in the mixture pulverizing step of P3 was 20 minutes.
0G20 composition is obtained, AP as a hard tissue-like cured body of living body
A C20G20 solid was obtained. The compressive strength of this cured product was measured by the method described above, and the surface state, calcium distribution, and composition were evaluated by the method described above. The results are shown in FIG. 4 and Table 1, as well as FIG. 6 (b), FIG. 7 (b), and FIG.
(B) is shown in Table 3.

In the same manner as in Example 2, the APC 20
APC20 G20 powder was obtained from G20 solid, and this APC
The X-ray diffraction results of 20G20 powder were evaluated by the method described above. The results are shown in FIG. 5 (g) and Table 2.

Comparative Example 2 A comparative powder composition was prepared in the same manner as in Example 3 except that the pulverizing time in the P3 mixture pulverizing step was set to 0 minutes, that is, the P3 mixture pulverizing step was not carried out. APC20 composition as a cured product was obtained, and APC20 solid as a comparative cured product was obtained. The compressive strength of this cured product was measured by the method described above, and the surface state, calcium distribution, and composition were evaluated by the method described above. The results are shown in FIG. 4 and Table 1, and FIG.
(A), FIG. 7 (a), FIG. 8 (a)-(c), and Table 3 are shown.

Further, as in the second embodiment, the APC 20
APC20 powder was obtained from the solid, and the X-ray diffraction result of this APC powder was evaluated by the method described above. The result is shown in Fig. 5.
(D) and shown in Table 2.

Example 5 A as a powder composition according to the present invention was prepared in the same manner as in Example 2 except that the amount of collagen added in the P2 mixing step was 10 parts by weight.
A PC10G20 composition was obtained to obtain an APC10G20 solid as a hard tissue-like cured body. This APC10G20
APC10G20 powder was obtained from the solid in the same manner as in Example 2, and the X-ray diffraction results of this APC10G20 powder were evaluated by the method described above. The results are shown in FIG. 5 (f) and Table 2.

Comparative Example 3 A comparative powder composition was prepared in the same manner as in Example 5 except that the pulverizing time in the P3 mixture pulverizing step was 0 minute, that is, the P3 mixture pulverizing step was not performed. APC10 composition as a cured product was obtained, and further APC10 solid as a comparative cured product was obtained.
From this APC10 solid, in the same manner as in Example 2, AP
C10 powder was obtained, and the X-ray diffraction result of this APC10 powder was evaluated by the method described above. The results are shown in FIG. 5 (c) and Table 2.

[Comparative Example 4] An AP composition as a conventional composition was obtained in the same manner as in Example 1 except that the steps after the mixing step of P2 above were not carried out. AP solid was obtained. From this AP solid, Example 2
AP powder was obtained in the same manner as above, and the X-ray diffraction result of this AP powder was evaluated by the method described above. The result is shown in FIG.
And shown in Table 2.

[0104]

[Table 1]

As is clear from the results shown in Table 1, in the cured product of the present invention, the compressive strength increased with the increase of the pulverization time, and as shown in FIG. 4, the amount of collagen added increased. However, it can be seen that the compressive strength increases. Therefore, it is understood that the compressive strength of the cured product according to the present invention can be controlled by changing the crushing time and the amount of collagen added, and the crushing time can also be controlled.

[0106]

[Table 2]

As is clear from the results shown in Table 2 and FIGS. 5 (a) to 5 (g), the powder of the hard body like a hard tissue according to the present invention has a diffraction peak seen near 2θ = 33 °. ing. That is, the powder of the hard tissue-like hardened body according to the present invention has a diffraction peak similar to the diffraction peak of the rat femur (FIG. 5 (h)), and is similar to the rat femur. Recognize. Particularly, as the amount of collagen added increases, the diffraction peak of the powder of the biological hard tissue-like cured body approaches the diffraction peak of the rat femur, so in the biological hard tissue-like cured body of the present invention, the amount of collagen added It is understood that the biological hard tissue-like property can be improved by increasing

On the other hand, the powder of the comparative cured product has a 2θ = 29-
It has a diffraction peak around 30 °, which is different from the diffraction peak of the rat femur, so that it is apparent that the biological hard tissue-like characteristic is low.

[0109]

[Table 3]

As is clear from the results shown in FIGS. 6 and 7 and Table 3, APC20G2 which is a cured product according to the present invention.
The surface state of 0 solid and the calcium distribution are shown in FIG.
It can be seen that it is very similar to that of the bovine bone shown in (c) and FIG. 7 (c). The region B shown in FIGS. 7B and 7C has the elemental composition shown in FIG. 8B, and it can be seen that the composition of the APC20G20 solid and the bone of the cow are similar.

On the other hand, it can be seen that the surface condition, calcium distribution, and composition of the APC20 solid, which is a comparative cured product, are different from those of bovine bone. Figure 7 of APC20 solid
The areas A, B, and C shown in FIG.
It has an element distribution as shown in (a), (b) and (c), and the region of B is similar to the above-mentioned APC20G20 solid and bovine bone. However, the region A has more carbon and the amounts of phosphorus and calcium less than those of the region B. In addition, collagen is present in a solid state.
Further, in the region C, more oxygen is present than in the region B, and calcium phosphate is solidified. That is, APC
It can be seen that the elemental composition of 20 solids does not have a uniform distribution but has variations.

Example 6 As a raw material, 500 mg of the APC20G20 composition obtained in Example 4 was collected,
0.2 mL of a 25 mM phosphoric acid aqueous solution was added (P4 curing control agent addition step), and kneaded well on a glass plate using a spatula (P5 kneading step). The resulting kneaded product has a diameter of 6 m
While filling the plastic cylinder of m with pressure,
It was left to stand for 24 hours in a constant temperature bath at a temperature of 100 ° C. and a relative humidity of 100% to be cured (curing step). Then, it was dried under reduced pressure for 24 hours to obtain a hard tissue-like body of the present invention having a diameter of 6 mm.
A disc-shaped APC20G20 cement having a size of 2 mm and a height of 2 mm was obtained.

A disk-shaped AP cement was obtained as a conventional cured product in the same manner as above except that the AP composition obtained in Comparative Example 4 was used as a raw material.

Then, a female Wister rat (4 weeks old) under anesthesia with ether was prepared, and the AP cement was subcutaneously placed on the left side of the rat on the right side as shown in FIG. 9 with the back vertebral bone as a boundary. 1 APC20G20 cement under the skin
It was administered individually. After that, a rat to which each cement was administered and a control rat to which nothing was administered were placed in a gauge, fed a normal diet and raised in the same environment. Then, 6 days, 23 days, 62 days, and 72 days after the cement administration, the bone mineral content (BMC) was measured (photographed) by the method described above.
The results are shown in Table 4, FIGS. 10 (a) to 10 (c) and FIG.

[0115]

[Table 4]

AP cement (spherical shape on the left side in FIGS. 10 (a) to 10 (c)) and APC20 administered to the back of the rat.
It can be seen that in the G20 cement (the spherical shape on the right side in the figure), calcium is eluted and the size of the cement becomes smaller as time passes on days 6, 23 and 72 after administration of the cement. In addition, the vertebral body bone is linear in the central portion of FIGS. 10 (a) to 10 (c).

The BMC of the cement before the administration of the above cement to rats was set to 100%, and APC20G was used.
As a result of examining the time-dependent change in BMC of 20 cement and AP cement, as shown in FIG. 11, it is found that both cements rapidly decrease until the 6th day and gradually decrease after the 6th day. Furthermore, when comparing the BMCs of the APC20G20 cement and the AP cement, it can be seen that the BMC of the APC20G20 cement containing collagen decreases more rapidly.

Example 7 A disk-shaped APC20 cement as a comparative cured product was obtained in the same manner as in Example 6 except that the APC20 composition obtained in Comparative Example 2 was used as a raw material.

Then, except that the APC20 cement was subcutaneously administered to the left side of the vertebral body bones of the rat and the APC20G20 cement was subcutaneously administered to the right side of the rat, respectively.
In the same manner as in Example 6, the bone mineral content (BMC) was measured (photographed) 6 days, 23 days, 62 days and 72 days after the cement administration by the method described above. The results are shown in Table 5 and FIG.
It shows in (a)-(c) and FIG.

[0120]

[Table 5]

APC20 cement (spherical shape on the left side in FIGS. 12 (a)-(c)) and AP administered to the back of the rat.
The size of C20G20 cement (spherical shape on the right side in the figure) becomes smaller with the lapse of 6 days, 23 days, and 62 days after the cement administration, and the APC20 cement disappears on the 62nd day. Can be understood (Fig. 12
(C)). Also, APC20G20 cement and AP
When the time-dependent change of BMC of C20 cement was measured,
As shown in FIG. 13, it rapidly decreased until the 6th day,
It can be seen that it gradually decreases after the first day.

Example 8 APC20G20 composition 50
In the same manner as in Example 6 except that 0.2 mL of a 25 mM phosphoric acid aqueous solution was added to 0 mg, and 2% by weight of VK ₂ having an osteoblast formation promoting action was further added and kneaded well.
As a hard tissue-like cured body according to the present invention, a disc-shaped A
PCGK ₂ cement was obtained.

Then, 6 times after the cement administration in the same manner as in Example 6 except that the APCGK ₂ cement was subcutaneously administered to the left side of the vertebral bone of the rat back and the APC20G20 cement was subcutaneously administered to the right side of the rat, respectively. 2 days later
Bone mineral content (BMC) after 3 days, 62 days, and 72 days was measured (taken) by the method described above. The results are shown in Table 6 and FIG.
(A) to (c) are shown in FIGS. 15 and 17.

[Comparative Example 5] In the same manner as in Example 8 except that the AP composition obtained in Comparative Example 4 or the APC20 composition obtained in Comparative Example 2 was used as a raw material, A disk-shaped APK ₂ cement or APCK ₂ cement was obtained as a comparative hardened body.

Then, the above-mentioned APK ₂ cement was subcutaneously placed on the left side of the vertebral body bone of the rat back, and the above-mentioned A was subcutaneously placed on the right side.
Example 6 except that PCK ₂ cement was administered one at a time
In the same manner as above, 6 and 23 days after the cement administration, 62
The bone mineral content (BMC) after 72 days was measured (photographed) by the method described above. The results are shown in Table 6, FIG. 16 and FIG.
Shown in.

[0126]

[Table 6]

From the results obtained in Example 8, the APCGK ₂ cement administered to the back of the rat (Fig. 14 (a)-
Regarding (c) the left sphere) and APC20G20 cement (the right sphere in the figure), it can be seen that the APCGK ₂ cement becomes larger 6 days after the cement administration. On the 23rd and 62nd days after cement administration, APCG was used.
K ₂ cement (the spherical shape on the left side in FIGS. 14 (b) and (c)) and APC20G20 cement (the spherical shape on the right side in FIG. 14)
It can be seen that the magnitude of is smaller with time.

When the time-dependent change of BMC of the cement was examined, as shown in FIG. 15, the BM of APCGK ₂ cement was examined.
It can be seen that C increases until the 6th day and gradually decreases after the 6th day. On the other hand, it can be seen that the APC20G20 cement rapidly decreases until the 6th day and gradually decreases after the 6th day.

Further, from the results obtained in Comparative Example 5, on the 6th day after the cement administration, the APK ₂ cement (the spherical shape on the left side in FIG. 16) was changed to the APCK ₂ cement (the spherical shape on the right side in FIG. 16). ) And APCGK ₂ cement (spherical shape on the left side of FIG. 14 (a)). This is because the APK ₂ cement does not contain collagen and therefore contains more calcium phosphate than the APCK ₂ cement.

Therefore, the BMC contained in each cement before administration to rats was set to 100%, and the BM of each cement was adjusted.
As a result of measuring the change with time of C, it can be seen that the BMC of APCK ₂ cement and APK ₂ cement which have not been crushed after the addition of collagen decreases with time. From the comparison with Example 8, the BMCs of APCK ₂ cement and APK ₂ cement were as shown in FIG.
It can be seen that the effect of increasing BMC by adding VK ₂ is not recognized. That is, it can be seen that the BMC increases when collagen is added and the P3 mixture pulverizing step is performed.

[Example 9] As a raw material, 500 mg of the APC5G5 composition obtained in Example 1 was collected, and
0.2 mL of mM phosphoric acid aqueous solution and indomethacin (I
MC) 25 mg was added and kneaded well. The obtained kneaded product was filled in a plastic cylinder having a diameter of 6 mm and a height of 12 mm, and while being pressurized, it was left to stand in a constant temperature bath at 37 ° C. and 100% relative humidity for 24 hours to be cured, and then dried under reduced pressure for 24 hours. went. Thus, as a drug carrier, which is one of the uses of the hard tissue-like cured body according to the present invention, a cylindrical APC5G5-IM having a diameter of 6 mm and a height of 12 mm is used.
A C carrier was obtained.

In the above APC5G5-IMC carrier
In vitro drug dissolution was measured by the method described above. The results are shown in FIG. 18 and Table 7.

[Examples 10 to 12] As the raw material, the above APC5G20 composition obtained in Example 2 and Example 3 were used.
The above APC20G5 composition obtained in Example 4, or Example 4
APC5G20-IMC carrier (Example 10), A was used as the drug carrier of the present invention in the same manner as in Example 9 except that the APC20G20 composition obtained in Example 1 was used.
PC20G5-IMC carrier (Example 11), or A
A PC20G20-IMC carrier (Example 12) was obtained.
The in vitro drug elution in each of these cylindrical drug carriers was measured by the method described above. The results are shown in FIG. 18 and FIG.
9, shown in Table 7.

[Comparative Examples 6 to 8] As a raw material, the APC5 composition obtained in Comparative Example 1, the APC20 composition obtained in Comparative Example 2, or the AP composition obtained in Comparative Example 4 was used. In the same manner as in Example 9 except that the substance was used, as a comparative drug carrier, an APC5-IMC carrier (Comparative Example 6), an APC20-IMC carrier (Comparative Example 7), or an AP-IMC carrier ( Comparative example 8) was obtained.
The in vitro drug elution in each of these cylindrical drug carriers was measured by the method described above. The results are shown in FIGS.
0, and also shown in Table 7.

[0135]

[Table 7]

From the results shown in FIGS. 18 to 20, all of these drug carriers show an increase in IMC release amount with time, and the solid sample having a shorter pulverization time in the P3 mixture pulverization step has a larger IMC release amount. I understand. Further, it can be seen that the greater the collagen content in the drug carrier, the greater the amount of IMC released.

[0137]

EFFECTS OF THE INVENTION The hard tissue-like cured body of the present invention comprises
As described above, in a hard tissue-like hardened body containing a biopolymer and a calcium phosphate compound, the biopolymer and a calcium-containing compound having a self-hardening composition are mixed and hardened. .

Therefore, since a biopolymer and a calcium-containing compound having a self-hardening composition are mixed and hardened, high biostability, biocompatibility, and high biodegradability are exhibited. There is an effect that can be.

The powder composition according to the present invention is a powder composition before the above-mentioned hardened body of hard tissue is hardened, and the powder composition contains phosphoric acid or phosphate as a main component. The above-mentioned hard tissue-like hardened product can be obtained by adding a kneading control agent containing water as a main solvent or water and kneading.

Therefore, since the curing can be further promoted by the addition of the curing control agent or water, it can be suitably used as a substitute material for living body hard tissue, a drug carrier for DDS, etc., and has high quality. An effect that a hard tissue-like cured body can be easily and surely obtained.

[Brief description of drawings]

FIG. 1 is a flow chart showing a process for producing a hard tissue-like cured body of the present invention.

FIG. 2 is a diagram showing an embodiment of a powder composition and a hard body-like hardened body according to the present invention, and the left diagram is a schematic diagram showing the structure of the powder composition after the P3 mixture pulverizing step. The right diagram is a schematic diagram showing the crystal structure of a hard tissue-like cured body of a living body produced by the powder composition being cured and transferred.

FIG. 3 is a diagram showing a powder composition and a hard tissue-like hardened body obtained when the mixture pulverizing step of P3 is not performed, and the left figure is a powder composition which is not subjected to the mixture pulverizing step of P3. The right figure is a schematic diagram showing the crystal structure of a hard body like a hard tissue in which the powder composition is cured and transferred.

FIG. 4 is a graph showing the results of measuring the compression strength of a cured product.

FIG. 5 is a powder X-ray diffraction spectrum of a powder sample.

6A is an electron micrograph of a solid surface of APC20, FIG. 6B is an electron micrograph of a solid surface of APC20G20, and FIG. 6C is an electron micrograph of bovine bone.

FIG. 7 (a) is a distribution diagram showing the calcium distribution of APC20 solids, (b) is a distribution diagram showing the calcium distribution of APC20G20 solids, and (c) is the calcium distribution of bovine bone. It is a distribution diagram shown.

8A is a graph showing the element distribution in the area A in FIG. 7A, and FIG. 8B is a graph showing B in FIGS. 7A to 7C.
7 is a graph showing the element distribution of the region, FIG.
It is a graph which shows the element distribution of C area | region in (a).

FIG. 9 is a schematic diagram showing a rat to which cement was administered.

FIG. 10 is a photograph of the back of a rat administered with APC20G20 cement and AP cement taken by a bone densitometer, (a) is a photograph of the back of a rat 6 days after the administration of cement, and (b) is , A photograph of the back of a rat on day 23, and (c) is a photograph of the back of a rat on day 72.

FIG. 11 is a graph showing the results of changes over time in bone mineral content of APC20G20 cement and AP cement administered to rats.

FIG. 12: APC20G20 cement and APC20
It is the photograph which image | photographed the back of the rat which administered the cement with the bone densitometer, (a) is a back photograph of the rat of the 6th day after cement administration, (b) is the back of the rat of the 23rd day. (C) is a photograph of the back of a rat on day 62.

FIG. 13 is a graph showing the results of changes over time in bone mineral content of APC20G20 cement and APC20 cement administered to rats.

FIG. 14: APCGK ₂ cement and APC20G2
It is the photograph which image | photographed the back of the rat which administered 0 cement with the bone densitometer, (a) is a back photograph of the rat of the 6th day after cement administration, (b) is the rat of the 23rd day. It is a back photograph, (c) is a back photograph of a 62-day-old rat.

FIG. 15 is a graph showing the results of time-dependent changes in bone mineral content of APCGK ₂ cement and APC20G20 cement administered to rats.

FIG. 16 is a photograph of the back of a rat taken on the 6th day with a bone densitometer, after APCK ₂ cement and APK ₂ cement were administered to the rat.

FIG. 17: APCGK ₂ Cement, A administered to rats
It is a graph which shows the result of the time change of the amount of bone minerals of PCK ₂ cement and APK ₂ cementment.

FIG. 18 is a graph showing the results of an indomethacin elution test of a drug carrier containing 5 parts by weight of collagen.

FIG. 19 is a graph showing the results of an indomethacin elution test of a drug carrier containing 20 parts by weight of collagen.

FIG. 20 is a graph showing the results of an indomethacin elution test of a drug carrier which was not subjected to the P3 mixture pulverizing step.

[Explanation of symbols]

1a Calcium Phosphate-Based Compound Particles (Calcium-Containing Compound) 1b Calcium Phosphate-Based Compound Particles (Calcium-Containing Compound) 2 Biopolymer 10 Transferred Compound (Calcium Phosphate-Based Compound)

Claims (12)

[Claims] 1. A hard tissue-like hardened body comprising a biopolymer and a calcium phosphate compound, wherein the biopolymer and a calcium-containing compound having a self-hardening composition are mixed and hardened. A hard tissue-like cured body. 2. A powder composition before the hard tissue-like cured body according to claim 1 is cured, wherein the powder composition contains phosphoric acid or a phosphate as a main component and water as a main solvent. The powder composition, wherein the hard tissue-like hardened product according to claim 1 is obtained by adding and kneading a hardening control agent or water. 3. The powder composition according to claim 2, wherein the biopolymer is a fibrous polymer contained in the connective tissue of a living body or a modified product thereof. 4. The powder composition according to claim 3, wherein the fibrous polymer is at least one of collagen and hyaluronic acid. 5. The calcium-containing compound is at least one of calcium hydrogen phosphate or its dihydrate, α-tricalcium phosphate, tetracalcium phosphate, and octacalcium phosphate. The powder composition according to claim 2, 3 or 4. 6. The calcium-containing compound is at least one of calcium-containing glass powder and calcium-containing glass crystallization powder, wherein the calcium-containing compound is at least one of calcium-containing glass powder and calcium-containing glass crystallization powder.
Or the powder composition according to 4. 7. When the weight of the biopolymer is 1,
The powder composition according to any one of claims 2 to 6, wherein the mixing ratio of the calcium-containing compound to the biopolymer is in the range of 0.1 or more and 10 or less by weight. 8. The powder composition according to any one of claims 2 to 7, wherein the calcium-containing compound contained in the powder composition is finally hydroxyapatite after curing. 9. The powder composition according to any one of claims 2 to 8, which further comprises a drug. 10. A powder composition according to any one of claims 2 to 9 is kneaded by adding a curing control agent containing phosphoric acid or a phosphate as a main component and water as a main solvent, or water. And a hardened body similar to a hard tissue. 11. A drug carrier comprising the powder composition according to any one of claims 2 to 9 on which a drug is carried and a curing control agent or water is added. 12. A biohard tissue-like cured body forming set containing the powder composition according to claim 2, further comprising at least one of the following a) or b): Tissue-like cured body formation set. a) A syringe for injecting a fluid or deformable kneaded product obtained by adding and kneading a hardening control agent or water and b) a hardening control agent or water.