JPH027930B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a therapeutic agent for fractures containing fibrinogen as an active ingredient, that is, a therapeutic agent that firmly joins fractured bones.

When tissue receives a wound, fibrinogen contained in blood flows out from the capillaries on the wound surface together with other blood components, fills the spaces between the tissues, and interacts with thrombin in the blood to form insoluble fibrin. It has the function of causing a stalemate. This agglutination effect facilitates the generation of fibroblasts on the wound surface, which eventually turn into fiber cells, fixing the tissue, and healing the wound surface. In this way, fibrinogen that is effective in healing wounds is fibrin membrane made by interacting with thrombin or dried fibrinogen (both approved by the Pharmaceutical Affairs Bureau of the Ministry of Health and Welfare and based on biological product standards).
The former is used as an artificial thin film to treat traumatic skin defects and burns, as well as in brain surgery, and the latter is used intravenously to treat hypofibrinemia. In addition, in recent years, in the field of surgery, there has been an increase in the need for extremely fine medical techniques and localized pharmacological action of the drugs used, such as anastomoses of fine tissues such as nerves and microvessels. fibrinogen preparation with strong adhesive force when administered locally (patent application 1983-
No. 36826) has also been developed.

The present inventors have conducted various studies to expand the use of fibrinogen in the surgical field, and as a result, have discovered that the tissue agglutination effect of fibrinogen is effective in joining fractured bones, and have completed the present invention. This bonding of bones by fibrinogen is completely different from the conventional uses of fibrinogen, and the present inventors have developed a new use for fibrinogen in the treatment of bone fractures.

In the present invention, fibrinogen is applied to the fracture surface, and then an adjuvant consisting of thrombin, a fibrinolytic enzyme inhibitor, and calcium chloride is applied, or thrombin and the adjuvant are simultaneously applied to the fracture surface, and fibrinogen is transferred to the fibrinogen by thrombin. The resulting fibrin acts as a "glue" to firmly connect fractured bones.

The present invention uses dry fibrinogen for medical use manufactured in accordance with the Biological Products Standards (1979, pp. 201-203) supervised by the Pharmaceutical Affairs Bureau of the Ministry of Health and Welfare, and is available as a commercially available product from Fibrinogen-Midori [Midori Co., Ltd.]. There is a powder with a cross. This product is made by adding coagulating proteins and stabilizers to dry fibrinogen, such as sodium citrate and monosaccharides such as glucose, glycose, fructose, and mannitol. Dissolve in buffer. This low salt concentration buffer is 0.01
~0.03 molar citrate buffer is preferred. The dissolution temperature is 32 to 36°C, and it is preferable to maintain a reduced pressure state in the bottle containing fibrinogen during dissolution. Under such dissolution conditions, dry fibrinogen powder dissolves within a range of about 2 to 10 W/V%. The higher the dissolved concentration, the better.

For clinical use, the fibrinogen solution prepared in this way is locally injected or applied depending on the application site (fracture site), and then supplemented with a mixture of thrombin, an inhibitor of fibrinolytic enzymes (aprotinin), and calcium chloride. Inject or apply the agent to the application site. This adjuvant may be added to the fibrinogen solution in advance. The dosage is 0.05 to 1 ml of fibrinogen solution with a concentration of 2 to 10% W/V per 1 cm ² of the junction, using the same amount of adjuvant. The respective activities of the adjuvants are thrombin 4~500U/ml, aprotinin 100~
5000KIE/ml, calcium chloride 10-100m
mole/ml.

The fracture treatment agent according to the present invention can be used not only for bone joining, but also for periosteum transplantation and periosteum joining.

Experimental examples and examples of the formulation of the present invention will be explained below.

Experimental Example 1 The bonding force of the formulation of the present invention was investigated using the bones of the extremities of pigs. 6% fibrinogen solution with pH 6 0.4
Thrombin 4U/ml and Aprotinin per ml
40mM calcium chloride solution containing 3000KIE/ml 0.4
ml and apply this to the fracture cross section of the fracture model at 0.1
ml/cm ² was injected to cement the bones. After standing overnight, the bonded bones were hung on a hand scale, the lower part was pulled vertically, and the force with which the bonded surfaces were sheared was read to measure the bond strength (g/cm ² ). The three cases tested were
It showed a bonding strength of 150 to 200 g/cm ² , confirming that this preparation is an excellent bone bonding agent.

Experimental Example 2 120g of medical human fibrinogen powder obtained from the ethanol fraction of corn contains 4.8g of glucose.
A fibrinogen preparation was obtained by adding g. Using this fibrinogen preparation, changes in bonding strength during bone bonding were measured over time by a method similar to Experimental Example 1. The bond strength in the fracture model reached a plateau 30 minutes after bonding, and the effect lasted for a long time. These results revealed that the fibrinogen preparation exerts a bonding effect in bone bonding in a short period of time, and that the effect lasts for a long period of time. The figure shows the change in bond strength over time.

Example: To an aqueous solution containing human fibrinogen obtained from the ethanol fraction of corn, coagulating proteins and sodium citrate and glucose as stabilizers were added, and after sterilization and UV irradiation, the solution was divided into bottles and freeze-dried. Then, a fibrinogen preparation containing 1 g of medical dry fibrinogen, 1 g of coagulable protein, 600 mg of sodium citrate, and 1600 mg of glucose is obtained in one bottle.

At the time of use, inject 12 ml of distilled water for injections into the bottle containing this fibrinogen preparation using a syringe, maintain a vacuum state inside the bottle, and heat the bottle to 32 to 36 degrees Celsius for approximately 20 minutes.
Shake for a minute to prepare a viscous, clear fibrinogen solution, which is transferred into a syringe.

Dilute 20ml of calcium chloride injection (2% solution) 2.6 times with distilled water for injections, and use this solution.
Dilute 74 ml of 5000 KIE/ml aprotinin injection 1.7 times to prepare a thrombin solution. thrombin
Add about 10 ml of the above thrombin solution to a bottle containing 500 units using a syringe to dissolve it, transfer to another container using a syringe, and add the thrombin solution to make the total volume 125 ml. 1 ml of this contains about 4 units of thrombin. This is used as an adjuvant.

[Brief explanation of drawings]

The drawing is a diagram showing changes in bonding strength over time.

Claims (1)

[Claims] 1. A fracture treatment agent consisting of a main agent containing fibrinogen as an active ingredient and an adjuvant mixture of thrombin, a fibrinolytic enzyme inhibitor, and calcium chloride.