JPH05339167A - Osteogenesis promoter - Google Patents

Abstract

PURPOSE:To provide the subject osteogenesis promoter containing a calcium- controlling hormone as the active component, excellent in osteogenesis and useful, e.g. for a patient who received trapsplantation of a bone marrow cell- porous ceramic composite. CONSTITUTION:The objective osteogenesis promoter contains a calcium- controlling hormone, e.g. calcitonin as the active component. In addition, the dosage of the calcium-controlling hormone is preferably within a range of 0.5mum to 1.0g per an adult per day.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an osteogenesis adjunct, and more particularly to an osteogenesis adjunct that exhibits high efficacy in osteogenesis in patients transplanted with porous ceramics containing bone marrow cells.

[0002]

2. Description of the Related Art Although bone cartilage formation is not observed by single subcutaneous transplantation of bone cells or single transplantation of porous ceramics (hydroxyapatite), it is necessary to see bone formation with hematopoietic function by transplantation of a composite of both. Has been reported. For example, research by Ogushi et al. Orthop. Res. 7,56
8-578, 1989; Acta Orthop. Scand. (6
1 (5), 431-434, 1990; Biomaterials. 1
2, 411-416. And J .; Biomed. Mat. Res. 24,
1563-1570, 1990. In order to realize this function, we have the presence of ceramics,
It is assumed that undifferentiated cells in the bone marrow differentiate into osteoblasts that have the ability to form bone, eventually leading to bone formation.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have investigated various agents that further promote osteogenesis in the composite of bone marrow cells and porous ceramics.

[0004]

[Means for Solving the Problems] Since it has been confirmed that bone formation in the above-mentioned ceramic is histologically and biochemically normal bone tissue, bone formation in this ceramic is systemic. It also reflects the bone formation ability in the.

That is, the present invention provides an osteogenesis aid containing a calcium-regulating hormone as an active ingredient.
As the calcium-regulating hormone used in the present invention, various conventionally known ones can be used. For example, vitamin D,
Examples thereof include bisphosphonate, ipripravone, estrogen, their derivatives, and calcitonin.
Among these, calcitonin exhibits the most excellent efficacy. Calcitonin that is already commercially available as a therapeutic drug for hypercalcemia is preferably used.

The osteogenic adjuvant of the present invention contains a calcium-regulating hormone, and the adjuvant may be in the form of tablets, capsules, powders, granules, orally or parenterally. It may be in the form of a liquid preparation such as a sterile solution or suspension for administration. Tablets, granules and powders are suitable for oral administration of the active ingredient of the present invention as necessary, and granules and powders can be administered as capsules as necessary.

Solid agents for oral administration include conventionally known formulation additives such as excipients (silicic acid anhydride, synthetic aluminum silicate, lactose, corn starch, microcrystalline cellulose, etc.) and binders (gum arabic, gelatin, polyvinyl). Pyrrolidone, hydroxypropyl cellulose, etc.), lubricants (magnesium steanphosphate, talc, silicic acid anhydride, etc.), and disintegrating agents (corn starch, carboxymethyl cellulose calcium, etc.) may be contained. The tablets may be coated according to a conventional method.

The liquid oral preparation may be in the form of an aqueous or oily suspension, solution, syrup or the like, but may also be a dried product which can be redissolved in a suitable solvent prior to use. Such liquid formulations are commonly used formulation additives, such as water, emulsifiers (lecithin, sorbitan monooleate, etc.), dispersion stabilizers (carboxymethyl cellulose sodium rim, gelatin, etc.), non-aqueous solvents (coconut oil, peanut oil, etc.). ), Antioxidants, colorants, flavors and the like. A liquid preparation may be obtained by dissolving or suspending a calcium-regulating hormone in a sterile solvent for use in parenteral administration. The solution may contain conventional buffering agents, isotonicity agents, solubilizing agents and the like.

The osteogenesis adjunct of the present invention is basically effective for any type of pathological disease, particularly for pathological diseases requiring promotion of osteogenesis. It shows extremely high osteogenicity for patients transplanted with porous ceramics. The effective dose of the calcium-regulating hormone varies depending on the patient's constitution and the like, but generally speaking, it is preferably in the range of 0.5 μg to 1.0 g per adult per day.

[0010]

EXAMPLES The present invention will be described in more detail by way of examples. The present invention is not limited to these examples. Example 1 In order to investigate the effect of the drug of the present invention, Calcified Tis. Int. in press. The method described in 1. was used. To summarize the summary, alkaline phosphatase (Alp) is said to be proportional to the activity of osteoblasts.
And bone-specific protein, which is said to be biosynthesized by osteoblasts, Bone Gla Protein (BGP)
Was quantified to observe the differentiation of undifferentiated cells into osteoblasts over time. For combined transplantation of ceramic and rat bone marrow, A
The LP activity started to increase from the second week after transplantation, peaked at the fourth week, and decreased at the sixth and eighth weeks. BGP is ALP
The activity began to increase one week after the activity, starting from the third week, and markedly increased at the peak of ALP activity (4 weeks), and then increased with time. In the demineralized histology, the osteoblast group detects a small amount of early bone formation at 2 weeks. From the 3rd week, clear bone formation was observed, which coincided with the appearance of BGP.

In the histological image of the 4th week having the highest ALP activity, a large number of active osteoblasts were found to be involved in osteogenesis in the ceramic pores. At 8 weeks, bone formation was further increased, but resting osteoblast was relatively increased. On the other hand, bone formation was not observed at all in the case of single transplantation of ceramic, and the amounts of ALP and BGP could be detected only in a trace amount. These results indicate that the transplantation of the rat bone marrow-ceramic composite material efficiently reproduced the new bone formation process. It is also shown that the process can be performed not only histologically but also biochemically.

The ceramic used has an average pore diameter of 200.
Hydroxyapatite with μ and 60% porosity
The shape was a disk with a diameter of 5 mm and a height of 2 mm. This time, this ceramic was used, but it has been found that other calcium phosphate-based ceramics also efficiently form bone by the complex with bone marrow cells. Bone marrow was collected from rat femur and tibia, mixed with ceramic, and then syngeneic (syngenei
c) Ceramics mixed with bone marrow were implanted subcutaneously on the back of 8-week-old male rats. The following two experiments were performed on rats implanted with these ceramics.

<Experiment 1> (A) The calcitonin preparation was intramuscularly injected 4 times a week from 2 weeks after the transplantation, and the ceramic was extracted 5 weeks after the injection. And 0.2% Nonid
Alkaline phosphatase (ALP) activity was measured using homogenate and centrifugation in et P40 and using the supernatant as the enzyme solution. In the control group, physiological saline was intramuscularly injected. (B) Also, 3 days after transplantation, the calcitonin preparation was intramuscularly injected four times a week, and the ceramic was removed 4 weeks later, and the same procedure as above was performed.
LP activity was measured. In the control group, physiological saline was intramuscularly injected. A total of 14 rats were used in both groups (A) and (B), and the total number of transplanted bone marrow-ceramic composites was 56.

<Experiment 2> Two months after transplantation, ovariectomy, and two months after ovariectomy, the ceramic was removed and decalcified with 20% formic acid.
Bone Gra Protein (BGP) was extracted and measured by RIA method. Some were fixed for tissue specimens. In the control group, only skin incision was performed, and ovariectomy was not performed. A total of 4 transplanted bone marrow-ceramic composites was used, using a total of 4 rats.

[0015]

[Results] As shown in Table 1, calcitonin treatment not only inhibited the osteoblast activity (alkaline phosphatase) during the osteogenesis process but also tended to increase it. As seen in Table 2, the amount of bone formation by ovariectomy (which reduces estrogen, a female hormone)
(BGP amount) decreased.

[0016]

[Table 1] Average alkaline phosphatase activity (μmole / 30 min / ceramic) Calcitonin treatment (intramuscular injection) Control ---------------------------- ------------------------------------- Experiment 1 (A) 4.84 4.1 Experiment 1 (B) 3.6 2.21 ---------------------------------------- ------------------------

[0017]

[Table 2] Average Bone Gra Protein Amount (ng / ceramic) Ovariectomized Control --------------------------------- ------------------------- Experiment 2 1874 3008 --------------------- -------------------------------------

Calcitonin preparations are well known to inhibit the process of bone resorption, but their effects on the process of bone formation are still unknown. The present experiment showed that it did not inhibit bone formation but tended to stimulate the bone formation process. Further, as seen in Experiment 2, it was found that the amount of new bone formation was reduced by decreasing the amount of the hormone estrogen.

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[Procedure amendment]

[Submission date] November 9, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be amended] Claims

[Correction method] Change

[Correction content]

[Claims]

Claims (3)

[Claims] 1. A bone formation aid containing a calcium regulating hormone as an active ingredient. 2. The bone formation auxiliary agent according to claim 1, wherein the calcium-regulating hormone is calcitonin. 3. The bone formation auxiliary agent according to claim 1, wherein the calcium regulating hormone is administered at a dose of 0.5 μg to 1.0 g per adult per day.