JPH0352304B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a bioterminal whose main part is made of an apatite material such as hydroxyapatite.

Conventional cannula (intubation) terminals have one end placed on the skin of the living body and the other end buried under the skin, and can be used for infusions, various drug solutions, etc., or artificial kidney dialysis through the through hole. Taking out the torrent of
It is used as an injection port, etc., and those made mainly of so-called bioinert materials such as silicone rubber and fluororesin have already been proposed.

However, these are nothing but foreign objects to the living body, and the parts of the living device are placed in a state of trauma, so they cannot be used for long periods of time due to bacterial infections etc. from the gap between the two. Not only is it completely unbearable, but it is also inferior in biosolidity and has several problems, such as concerns about bleeding due to shaking, so it has not yet been widely used.

For example, the so-called drug delivery system (Klaus Heilman, ``Drug Delivery System'', Showa), which has seen remarkable progress in recent years, such as the artificial pancreas, etc.
(Refer to Ibakuyaku Publishing, published in 1958, etc.), the issue of the injection route for drugs such as insulin remains unresolved (see Igaku Gakushu, Vol. 53, No. 2, p. 90 et seq., 1982). It can be said that the desire for a bioterminal that can be used semi-permanently and safely as a drug injection port is increasing even more these days.

On the other hand, in recent years, the excellent biocompatibility and osteoinductivity of apatite-based materials such as sintered hydroxyapatite have been elucidated, and the use of sintered bodies for artificial tooth roots and artificial bones has been proposed and put into practice. However, the physiological reactivity of the sintered body with skin tissue is completely unknown in the prior art.

In view of the above, the present inventors conducted extensive research and surprisingly found that apatite-based materials such as sintered hydroxyapatite not only have an affinity for skin tissues, but also bond closely and integrally with these tissues. The present invention was achieved by discovering this fact.

Hereinafter, the material composition, manufacturing method, shape and structure, mode of use, etc. of the bioterminal, plug, or conduit of the present invention will be explained in detail.

Material Composition/Manufacturing Method In the present invention, the "apatite material" refers to not only hydroxyapatite whose chemical composition is represented by Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ but also 1 to 10% of hydroxyapatite instead of OH ions. Carbonate (CO ₃ ) ions, fluorine, chloride ions, and their various ion-substituted products that may contain Mg instead of Ca, or those based on these, improve sinterability, strength, porosity, etc. This should include Ca ₃ (PO ₄ ) ₂ , Ca ₄ O (PO ₄ ) ₂ ,
_MgO , _Na2O , _K2O , _CaF2 , _Al2O3 , _SiO2 ,
CaO, Fe ₂ O ₃ , MnO, MnO ₂ , ZnO, C, SrO,
It also includes mixtures of various known additives such as PbO, BaO, TiO ₂ , ZrO ₂ or various polymeric materials.

Here, when using a composite agent with a polymer, relatively less toxic polyethylene, polyprolene, polymethyl methacrylate, polyurethane, polyester, ABS resin, fluorine resin, polycarbonate, polysulfone, epoxy resin, silicone resin, diallyl phthalate are used. You can choose resin such as resin or furan resin.

On the other hand, examples of manufacturing methods include a so-called sintering method on a single body or a base material such as metal, and a plasma injection method on a base material such as metal. For example, the single sintered body is generally made of hydroxyl. Apatite powder is 500-3000Kg/cm ² by mold or rubber press etc.
It is obtained by compression molding into a desired shape under a certain amount of pressure, and then sintering it at a temperature of about 700 to 1300°C.For more details, including other manufacturing methods and compositions, refer to the following known techniques. is referenced. That is, JP-A No. 51-40400, No. 52-64199, No. 52-
82893, 52-142707, 52-147606, 52-
149895, 53-28997, 53-75209, 53-
111000, 53-118411, 53-144194, 53-
110999, 54-158099, 55-51751, 55-
130854, 55-140756, 56-45814, 56-
166843, Special Publications No. 57-40776 and No. 57-40803.

The relative density (based on the density of hydroxyapatite single crystal) of the sintered body that is particularly useful in the present invention from the viewpoint of bondability with skin tissue is 60 to 60.
It is more preferably about 85 to 95% than 99.5%.

Shape or Structure The bioterminal configuration of the present invention can be made into any desired configuration depending on the purpose of use, and a typical example thereof will be described in detail with reference to the accompanying drawings as follows.

That is, FIG. 1 is a sectional view showing one example of the bioterminal of the present invention, and in the figure, the bioterminal used as a drug injection port has a terminal head part 2 and a terminal bottom part 3, both of which are made of a sintered hydroxyapatite body. A cylindrical body 5 made of metal or synthetic resin such as silicone resin is provided with a sterilizing membrane filter 4 such as a Millipore filter inside or at the end thereof. The desired drug is injected into the living body through the through hole 6.

On the other hand, since apatite-based materials such as sintered hydroxyapatite bodies (materials) can achieve the desired purpose if they are interposed in the contact area with the skin tissue, it is possible to form only the essential parts of the bioterminal with such materials. It may be made of a different material such as synthetic resin, or the main part may be made of apatite sintered covering material (Japanese Patent Application Laid-open No.
82893, No. 53-75209, No. 53-118411, etc.).

For example, a microtube formed by forming a sprayed or sintered layer of hydroxyapatite on the outer periphery of a micrometallic tube can be used as a bioterminal.

FIG. 2 is a cross-sectional view of a microtubular bioterminal,
A sintered hydroxyapatite coating layer or a sprayed layer 8 is formed on the outer periphery of a metal bottom 7 such as a brass tube, and the filter 1
0 is connected to the end of the sterilizing filter means 9, and is used by simply being embedded and fixed in the patient's skin.

As is clear from the above, the bioterminal of the present invention can have various shapes, structures, and dimensions, and is not limited to a specific form.

Mode of use As mentioned above, according to the present invention, a bioterminal made of an apatite material such as a sintered hydroxyapatite body is not only biocompatible but also interfacially bonded with skin tissues such as the epidermis and dermis, and is stably fixed in a living body. Since it has been clarified that it is a biological terminal, it can be widely applied as a drug input port in various drug delivery systems.
It is sufficient to simply connect a tube or the like into which a chemical liquid quantitatively driven by a micro pump or the like is inserted.

Here, a particularly useful mode of use of the bioterminal of the present invention is its use as an injection port for so-called iontophoresis (iontophoresis therapy) in which drugs are driven electrochemically.

For example, insulin and HCl in conventional artificial pancreas
The injection of insulin was performed using a micrometer injection pump (see the above-mentioned medical journal), but instead of this, the implant terminal of the present invention can be simply electrically connected to the anode of a DC power source to inject insulin and cations. can be introduced into a living body extremely easily and safely.

This is because conventional iontophoresis is performed on the skin, but in that case the stratum corneum serves as an electrical and physical barrier layer, making it difficult to introduce relatively large molecules such as insulin. According to the bioterminal of the present invention, the stratum corneum of the skin can no longer serve as a barrier, resulting in significant impedance and physical resistance, and the current value (normally, in the case of insulin, a few μA of direct current or pulsed direct current) (within the range of several mA), quantitative or feedback injection using a glucose sensor can be easily achieved.

That is, when the bioterminal of the present invention is used in iontophoresis, it is possible to use an implant bioterminal instead of the chemical solution impregnated conductor (generally made of water retaining material such as sponge or cotton or hydrophilic gel material) used in conventional iontophoresis. A drug solution injection conduit is connected to the terminal to form a seki conductor, and various well-known bioelectrodes (e.g.
Japanese Patent Publication No. 58-10066 or Japanese Patent Application No. 56-106935,
It is sufficient to attach a non-conducting conductor made of (see) to another part of the skin and passing a direct current between the two (if the ionic drug is a cation, a non-conducting conductor anode, etc.).

For details of the iontophorase itself, refer to the description in the above-mentioned publication.

Hereinafter, the present invention will be explained in detail with reference to Examples.

Experimental example 1 1 Structure of bioterminal Hydroxyapatite powder is 0.5 mol/
Gradually drop 0.3 mol of calcium hydroxide/phosphoric acid solution and react at 37℃ for 1 day to synthesize.
This was obtained by filtering and drying. This synthetic powder was filled into a mold and compression molded at a pressure of 800 kg/cm ² to form a mold with a diameter of 2.
A green compact was obtained which had through holes of mm in diameter and a bulk density of 1.6 g/cm ³ . This was cut and processed into the terminal head shape (see Figure 1) using a lathe and a dental diamond bur. Similarly, the synthetic powder was filled into a mold, compression molded, and cut to form a terminal bottom (see FIG. 1). Next, the through-holes of both compacts were joined together, and gel-like apatite powder, which had been thoroughly kneaded in a mortar with water added in advance, was applied between the two to bond them together.
This was sintered at 1250℃ for 1 hour to achieve compressive strength.
5000Kg/cm ² , bending strength 1200Kg/cm ² , relative density 95
A bioterminal as shown in FIG. 1 was obtained in which the adhesive portion was uniformly sintered.

Here, the terminal bottom has a diameter of 5.4 mm and a thickness of 2 mm, and the terminal head and neck have a diameter of 4 mm and an inner diameter of 2 mm.
It is.

The sintered body obtained when the sintering temperature is 1100℃ has a relative density of 85% and a compressive strength of
It had a bending strength of 3000Kg/cm ² and a bending strength of 700Kg/cm ² . still,
Finally, a sterilizing filter means disposed in a synthetic resin cylinder was installed inside the terminal as shown in FIG. 1 to prepare a sample.

2 Animal experiment The above bioterminal was implanted in the skin of the flank of an adult mongrel dog, and observation over time revealed that the terminal was strongly bonded to the skin tissue at the bottom and neck area about 2 weeks after the surgery, and was pulled. Even after one year, no abnormal findings such as inflammatory reactions were observed with the naked eye.

In addition, no inflammatory cells were found in normal histological examination.

On the other hand, in the case of a control silicone rubber terminal of the same shape, no adhesion to the skin was observed even 4 weeks after the operation, and inflammatory redness was already observed. Moreover, in the second month, the inflammation progressed and it began to suppurate, and in the third month, it fell off.

Experimental example Additives to the hydroxyapatite powder include Ca ₃ (PO ₄ ) ₂ 7%, MgO, 0.8%, Na ₂ O 1.8%,
A _small cylindrical sintered body (outside diameter 3
mm) was prepared and polished with an abrasive material to obtain a microtubular terminal having the shape shown in the attached FIG. 2.

The length of the sintered part of this terminal is 8 mm, and the outer diameter is 2 mm.
It was hot.

Next, a sterilization filter means was connected to this as shown in Fig. 2, and then it was punctured and buried in the chest of an adult dog so that its tip was located subcutaneously.After about 3 weeks, it completely joined with the skin tissue. It became a fixed state.

Therefore, we connected the terminal end to a conduit filled with physiological saline and measured the DC resistance (as an indifferent conductor, an electrocardiogram electrode LECTRODE made by Advance Electrode was attached to another shaved chest). use),
A value of 1.7kΩ was obtained. Compared to the skin resistance through the stratum corneum, which is normally about 100 kΩ, a significant decrease is observed.

[Brief explanation of drawings]

Attached Figures 1 and 2 are schematic cross-sectional views of the bioterminal of the present invention. ,...Biological terminal for drug treatment system, 2...
...Terminal head, 3... Terminal bottom, 4, 10... Sterilization filter, 5, 9... Cylindrical body, 6... Through hole.

Claims (1)

[Scope of Claims] 1. A medicinal device characterized in that at least the part in contact with the skin tissue is made of an apatite-based material, a filter means for bacterial protection is provided inside and at the end, and a medicinal solution passageway is provided. Bioterminal for skin treatment system. 2. An iontophoresis device consisting of a bioterminal for a transdermal treatment system, in which at least the part in contact with skin tissue is made of an apatite-based material, a filter means for bacterial protection is provided inside and at the end, and a medicinal fluid conduction path is provided. Terminal for Reese.