JPH0150416B2 - - Google Patents
Info
- Publication number
- JPH0150416B2 JPH0150416B2 JP58166502A JP16650283A JPH0150416B2 JP H0150416 B2 JPH0150416 B2 JP H0150416B2 JP 58166502 A JP58166502 A JP 58166502A JP 16650283 A JP16650283 A JP 16650283A JP H0150416 B2 JPH0150416 B2 JP H0150416B2
- Authority
- JP
- Japan
- Prior art keywords
- bioterminal
- sintered
- drug
- terminal
- skin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 239000000463 material Substances 0.000 claims description 26
- 239000003814 drug Substances 0.000 claims description 18
- 229940079593 drug Drugs 0.000 claims description 18
- 229910052586 apatite Inorganic materials 0.000 claims description 9
- VSIIXMUUUJUKCM-UHFFFAOYSA-D pentacalcium;fluoride;triphosphate Chemical compound [F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O VSIIXMUUUJUKCM-UHFFFAOYSA-D 0.000 claims description 9
- 239000012530 fluid Substances 0.000 claims 1
- 210000003491 skin Anatomy 0.000 description 15
- 238000002347 injection Methods 0.000 description 12
- 239000007924 injection Substances 0.000 description 12
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 12
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 10
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 10
- 239000011148 porous material Substances 0.000 description 8
- 239000010410 layer Substances 0.000 description 7
- 239000012528 membrane Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 102000004877 Insulin Human genes 0.000 description 6
- 108090001061 Insulin Proteins 0.000 description 6
- 230000004888 barrier function Effects 0.000 description 6
- -1 fusosine Chemical class 0.000 description 6
- 229940125396 insulin Drugs 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 229920005989 resin Polymers 0.000 description 6
- 239000011347 resin Substances 0.000 description 6
- 239000004020 conductor Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 4
- 238000005452 bending Methods 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 238000000502 dialysis Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007943 implant Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000005245 sintering Methods 0.000 description 3
- 210000000434 stratum corneum Anatomy 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000004809 Teflon Substances 0.000 description 2
- 229920006362 Teflon® Polymers 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 238000005370 electroosmosis Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 2
- 229920002492 poly(sulfone) Polymers 0.000 description 2
- 229920000515 polycarbonate Polymers 0.000 description 2
- 239000004417 polycarbonate Substances 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 239000004926 polymethyl methacrylate Substances 0.000 description 2
- 229920002050 silicone resin Polymers 0.000 description 2
- 229920002379 silicone rubber Polymers 0.000 description 2
- 239000004945 silicone rubber Substances 0.000 description 2
- 229920003002 synthetic resin Polymers 0.000 description 2
- 239000000057 synthetic resin Substances 0.000 description 2
- 238000000108 ultra-filtration Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 229910001369 Brass Inorganic materials 0.000 description 1
- 229910014497 Ca10(PO4)6(OH)2 Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- UNPLRYRWJLTVAE-UHFFFAOYSA-N Cloperastine hydrochloride Chemical compound Cl.C1=CC(Cl)=CC=C1C(C=1C=CC=CC=1)OCCN1CCCCC1 UNPLRYRWJLTVAE-UHFFFAOYSA-N 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 239000004641 Diallyl-phthalate Substances 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N Na2O Inorganic materials [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000003082 abrasive agent Substances 0.000 description 1
- 229920000122 acrylonitrile butadiene styrene Polymers 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- QUDWYFHPNIMBFC-UHFFFAOYSA-N bis(prop-2-enyl) benzene-1,2-dicarboxylate Chemical compound C=CCOC(=O)C1=CC=CC=C1C(=O)OCC=C QUDWYFHPNIMBFC-UHFFFAOYSA-N 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000010951 brass Substances 0.000 description 1
- WUKWITHWXAAZEY-UHFFFAOYSA-L calcium difluoride Chemical compound [F-].[F-].[Ca+2] WUKWITHWXAAZEY-UHFFFAOYSA-L 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 229910001634 calcium fluoride Inorganic materials 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000011247 coating layer Substances 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000000748 compression moulding Methods 0.000 description 1
- 229910052593 corundum Inorganic materials 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 239000003822 epoxy resin Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007849 furan resin Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000010562 histological examination Methods 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 150000002605 large molecules Chemical class 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- VASIZKWUTCETSD-UHFFFAOYSA-N manganese(II) oxide Inorganic materials [Mn]=O VASIZKWUTCETSD-UHFFFAOYSA-N 0.000 description 1
- 238000001471 micro-filtration Methods 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 230000037311 normal skin Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 238000007750 plasma spraying Methods 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920002239 polyacrylonitrile Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920000647 polyepoxide Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 229910052573 porcelain Inorganic materials 0.000 description 1
- 239000005373 porous glass Substances 0.000 description 1
- NOTVAPJNGZMVSD-UHFFFAOYSA-N potassium monoxide Inorganic materials [K]O[K] NOTVAPJNGZMVSD-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000004627 regenerated cellulose Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- 229910001845 yogo sapphire Inorganic materials 0.000 description 1
- XLOMVQKBTHCTTD-UHFFFAOYSA-N zinc oxide Inorganic materials [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 1
Description
【発明の詳細な説明】
本発明はその要部がハイドロキシアパタイト等
のアパタイト系材より成る生体端子に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a bioterminal whose main part is made of an apatite material such as hydroxyapatite.
従来のcannula（挿管）といつた生体用端子は
その一端が生体皮膚上にあり他端が皮下に埋設さ
れて、その貫通孔を介して輸液、各種薬液等の注
入又は人工腎臓透析等のための血流の取り出し、
注入口等として使用されるものであり、主として
シリコーンゴム、ふつ素樹脂等の所謂生体不活性
材より形成されたものが既に提案されている。 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. withdrawal of blood flow from
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.
しかし乍らこれらは生体にとつてはあくまでも
異物に他ならずその生体装着部位は一種の外傷を
受けた状態に置かれるものとなるので両者の間隙
からの細菌感染等により長時間の使用には到底耐
え得ないものであるのみならず、生体固定性に劣
るため例えば揺動による出血の心配等、幾つかの
問題を有するものであるため未だ充分に普及し得
ないものとなつている。 However, these are nothing but foreign objects to the living body, and the part where they are attached to the living body is left 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 extremely difficult to withstand, but it also has several problems, such as concerns about bleeding due to shaking due to its inferior biofixability, so it has not yet been widely used.
例えば人工膵臓等の近時その発展が著るしい所
謂薬物治療（ドラツグ・デリバリ）システム（ク
ラウス・ヘイルマン著「薬物治療システム」昭和
58年医菌薬出版発行等、参照）にあつては、イン
スリン等に薬物の注入経路及び極微量定量注入法
等の問題が未解決であり（医器学誌昭和58年第53
巻第２号第90頁以下参照）、薬物注入口として半
恒久的且つ安全に使用し得る生体端子への希求は
今日一段と高まつているものと云えよう。 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 Shuppan, published in 1980), the issues such as the route of injection of drugs such as insulin and the method of injecting extremely small amounts are unresolved.
(See Vol. 2, No. 2, pp. 90 et seq.), and 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.
他方、近時ハイドロキシアパタイト焼結体等の
アパタイト系材の優れた生体親和性、更には骨誘
導性が解明されると共にその焼結体による人工歯
根、人工骨への利用が提案、実用されつつある
が、同焼結体の皮膚組織との生理学的反応性につ
いては先行技術に於いて全然未解明である。 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.
上記に鑑み本発明者らは鋭意研究の結果、驚く
べきことにハイドロキシアパタイト焼結体等のア
パタイト系材は皮膚組織に対し単に親和性を有す
るのみならずこれら組織と緊密且つ一体的に接合
するという事実並びに前記定量注入は薬物の自然
拡散を可及的に阻止する生体組織と接したバリヤ
層の配設により容易に解決されることを知見し、
本発明に到達したものである。 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. and the fact that the above-mentioned metered injection can be easily solved by providing a barrier layer in contact with the living tissue to prevent the natural diffusion of the drug as much as possible,
This has led to the present invention.
以下、本発明生体端子乃至栓或いは、導管につ
きその材料組成及び製法、形状乃至構造、使用の
態様等につき詳細に分説する。 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.
材料組成・製法
１ 本発明に於ける“アパタイト系材”とはその
化学組成がCa10（PO4）6（OH）2で表わされるハ
イドロキシアパタイトのみならず、OHイオン
のかわりに１〜10％のカーボネート（CO3）イ
オンやフツソ、塩素イオン或いはそのCaの代
わりにMg等を含むこともあるその各種イオン
置換体、或いはこれらを主成分とするも焼結
性、強度、細孔度等を向上すべくこれにCa3
（PO4）2、Ca4O（PO4）2、MgO、Na2O、K2O、
CaF2、Al2O3、SiO2、CaO、Fe2O3、MnO、
MnO2、ZnO、Ｃ、SrO、PbO、BaO、TiO2、
ZrO2又は各種高分子材料等々の周知各種添加
剤を添加混合したものをも包含する。Material composition/manufacturing method 1 The "apatite-based material" in the present invention is not only hydroxyapatite whose chemical composition is represented by Ca 10 (PO 4 ) 6 (OH) 2 but also 1 to 10% of OH ions instead of OH ions. carbonate (CO 3 ) ions, fusosine, chlorine ions, various ion substituted products thereof that may contain Mg etc. instead of Ca, or materials containing these as main components, but with improved sinterability, strength, porosity, etc. Ca 3 to this to improve
( PO4 ) 2 , Ca4O ( PO4 ) 2 , MgO, Na2O , K2O ,
CaF2 , Al2O3 , SiO2 , CaO, Fe2O3 , MnO ,
MnO2 , ZnO, C, SrO, PbO, BaO, TiO2 ,
It also includes mixtures with various well-known additives such as ZrO 2 or various polymeric materials.
ここで、高分子との複合剤とする場合は、比
較的毒性の少ないポリエチレン、ポリプロピレ
ン、ポリメチルメタクリレート、ポリウレタ
ン、ポリエステル、ABS樹脂、フツ素樹脂、
ポリカーボネート、ポリスルホン、エポキシ樹
脂、シリコン樹脂、ジアリルフタレート樹脂、
フラン樹脂等の樹脂を選ぶことができる。 Here, when using a composite agent with a polymer, relatively less toxic polyethylene, polypropylene, polymethyl methacrylate, polyurethane, polyester, ABS resin, fluororesin,
Polycarbonate, polysulfone, epoxy resin, silicone resin, diallyl phthalate resin,
Resins such as furan resin can be selected.
他方、その製造法としては単体或いは金属等
の基材上で所謂焼結法を始めとして金属等の基
材へのプラズマ溶射法等を例示し得、例えばそ
の単独焼結体は一般にハイドロキシアパタイト
粉末を金型又はラバープレス等により500〜
3000Kg／cm2程度の圧力下、所望の形状に圧縮成
形し、次いでこれを700〜1300℃程度の温度で
焼結処理して得られるものであるが、その他の
製法及び組成を含めてより詳細は下記公知技術
が参照される。すなわち、特開昭51−40400、
同52−64199、同52−82893、同52−142707、同
52−147606、同52−149895、同53−28997、同
53−75209、同53−111000、同53−118411、同
53−144194、同53−110999、同54−158099、同
55−51751、同55−130854、同55−140756、同
56−45814、同56−166843、特公昭57−40776及
び同57−40803号各公報。 On the other hand, examples of manufacturing methods include a so-called sintering method on a single body or a base material such as a metal, and a plasma spraying method on a base material such as a metal. For example, the single sintered body is generally made of hydroxyapatite powder. 500 ~ by mold or rubber press etc.
It is obtained by compression molding into the desired shape under a pressure of about 3000 kg/cm 2 and then sintering it at a temperature of about 700 to 1300°C, but more detailed information including other manufacturing methods and composition is available. The following known techniques are referred to. That is, JP-A-51-40400,
Same 52-64199, Same 52-82893, Same 52-142707, Same
52-147606, 52-149895, 53-28997, same
53-75209, 53-111000, 53-118411, same
53-144194, 53-110999, 54-158099, same
55-51751, 55-130854, 55-140756, same
No. 56-45814, No. 56-166843, Special Publication No. 57-40776 and No. 57-40803.
尚、皮膚組織との接合性という観点から本発
明に於いて特に有用な焼結体の相対密度（ハイ
ドロキシアパタイト単結晶の密度を基準）は、
60〜99.5％、より好ましくは85〜95％程度であ
る。 The relative density (based on the density of hydroxyapatite single crystal) of the sintered body, which is particularly useful in the present invention from the viewpoint of bondability with skin tissue, is as follows:
It is about 60 to 99.5%, more preferably about 85 to 95%.
２ 本発明に於ける“多孔性部材”は、薬液導通
路への生体組織の侵入並びに薬物の自然濃度拡
散に対するバリヤ層として機能し得るものであ
り、多孔性テフロンフイルム等の多孔性樹脂フ
イルム、濾材乃至濾膜として使用されている多
種多孔性樹脂焼結材、多孔性アルミナ焼結材等
の多孔性セラミツクス、多孔性ガラス、白金焼
結体等の多孔性金属焼結体、電解工業分野で使
用されている磁製隔膜等の各種電気化学的隔
膜、透析膜、更には前掲各公報にも記載の多孔
性リン酸カルシウム素材等々、適度な平均孔径
を有するフイルム状、シート状、円柱状等々の
各種形状の多孔性材料が使用目的に応じて適宜
選択使用される。2. The "porous member" in the present invention can function as a barrier layer against the intrusion of living tissue into the drug solution channel and the natural concentration diffusion of the drug, and includes porous resin films such as porous Teflon films, Various porous resin sintered materials used as filter media or filter membranes, porous ceramics such as porous alumina sintered materials, porous glass, porous metal sintered materials such as platinum sintered materials, and electrolytic industry fields. Various types of electrochemical diaphragms such as the porcelain diaphragms used, dialysis membranes, porous calcium phosphate materials described in the above-mentioned publications, etc., in the form of films, sheets, cylinders, etc. with appropriate average pore diameters. Porous materials of various shapes are appropriately selected and used depending on the purpose of use.
ここに於いて、多孔性部材の前記バリヤ層と
しての作用を考慮すれば、通常、その平均孔径
は0.01μ〜１mm、より好ましくは0.5μ〜700μの
範囲内で選択されるものであるが、一般にはイ
ンプラント部位、深度及び使用薬物の分子量、
濃度、更には薬物注入に用いるエネルギー形態
等々により変更自在である。 Here, in consideration of the function of the porous member as the barrier layer, the average pore diameter is usually selected within the range of 0.01μ to 1mm, more preferably 0.5μ to 700μ, In general, the implant site, depth and molecular weight of the drug used,
It can be changed freely depending on the concentration, energy form used for drug injection, etc.
特に、再生セルロース、ポリアクリロニトリ
ル、ポリメチルメタクリレート、セルロースア
セテート、ポリカーボネート、ポリスルホン、
ポリアミド等々の分画分子量１万〜５万程度の
人口透析用等の各種限外濾過膜或いは平均孔径
0.5μ〜100μ程度の濾過乃至精密濾過膜を本発明
多孔性部材として使用する場合は、前記バリヤ
層としての機能は充分としても、濾過抵抗が大
きいため薬物の注入エネルギーとして圧力等の
機械的エネルギーを用いることは必ずしも好ま
しくなく、この場合は後記イオントフオレーゼ
乃至電気浸透法等の電気化学的駆動力の使用が
好適となる。例えば、電気浸透は周知の通り細
孔を有する多孔体に電圧を印加すれば界面電気
化学的原理により陰陽極のいずれかに液体が定
量的に移動する現象であり、本発明生体端子は
この種の方法へも適用され得るものであり、こ
の場合は、界面電気化学的性質を考慮して薬液
と多孔性部材とが組み合わせ選択される。 In particular, regenerated cellulose, polyacrylonitrile, polymethyl methacrylate, cellulose acetate, polycarbonate, polysulfone,
Various ultrafiltration membranes for population dialysis, etc. with a molecular weight cutoff of 10,000 to 50,000, such as polyamide, etc., or average pore diameter
When using a filtration or microfiltration membrane of about 0.5μ to 100μ as the porous member of the present invention, even if the function as the barrier layer is sufficient, the filtration resistance is large, so mechanical energy such as pressure is used as the energy for drug injection. It is not necessarily preferable to use this method, and in this case, it is preferable to use an electrochemical driving force such as iontophoresis or electroosmosis method described later. For example, as is well known, electroosmosis is a phenomenon in which when a voltage is applied to a porous body having pores, liquid is quantitatively transferred to either the cathode or the anode due to the interfacial electrochemical principle, and the bioterminal of the present invention is of this type. In this case, the combination of the chemical solution and the porous member is selected in consideration of the interfacial electrochemical properties.
形状乃至構造
本発明生体端子の形態は使用目的に応じて所望
のものとなし得るが、その典型例につき添付図面
を参照して詳説すれば次の通りである。Shape and Structure The bioterminal of the present invention can have any desired shape depending on the purpose of use, and typical examples thereof will be described in detail below with reference to the accompanying drawings.
すなわち、第１図は本発明生体端子の１例を示
す断面図であり、図中、薬物注入口として使用さ
れる生体端子は共にハイドロキシアパタイト焼
結体より成る端子頭部２と同底部３とを一体的に
結合して成るものであり、その内部又は端部に例
えばAmiconPM―30、0.22μミリポアメンブラン
フイルタ等の限外濾過膜、或いは平均径15μのポ
リエチレン焼結体フイルタ等の多孔性部材４を備
えた金属製又はシリコーン樹脂製等の合成樹脂製
筒体５を装着して成るものであり、その貫通孔６
を介して所望薬物が生体内に注入される。他方、
ハイドロキシアパタイト焼結体（材）等のアパタ
イト系材は皮膚組織との接触部分に介在すれば所
定の目的を達成し得るのであるから、生体端子の
要部のみを当該材で形成し他を合成樹脂等の異種
材で構成するようにしてもよく、或いはその要部
をアパタイト焼結被覆材（特開昭52−82893号、
同53−75209号及び同53−118411号公報等、参照）
で形成してもよい。 That is, FIG. 1 is a cross-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 2 and a terminal bottom 3 made of a sintered hydroxyapatite body. An ultrafiltration membrane such as Amicon PM-30, 0.22μ millipore membrane filter, or a porous member such as a polyethylene sintered filter with an average diameter of 15μ is attached inside or at the end of the membrane. 4, which is equipped with a cylindrical body 5 made of metal or synthetic resin such as silicone resin, which has a through hole 6.
The desired drug is injected into the living body via. On the other hand,
Since apatite-based materials such as sintered hydroxyapatite (materials) can achieve the desired purpose if they are interposed in the contact area with the skin tissue, only the essential parts of the bioterminal are formed from this material, and the rest are synthesized. It may be made of a different material such as resin, or the main part may be made of apatite sintered covering material (Japanese Patent Application Laid-Open No. 52-82893,
(See Publications No. 53-75209 and No. 53-118411, etc.)
It may be formed by
例えば微小金属管外周にハイドロキシアパタイ
ト溶射乃至焼結層を形成して成る微小管を生体端
子として使用し得る。 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.
第２図は微小管状生体端子の断面図であり、
金管等の金属管７の外周にハイドロキシアパタイ
ト焼結被覆層乃至溶射層８を形成し、平均孔径
3μのアルミナ焼結体より成る多孔性部材９を端
部に連結して成るものであり、患者の皮膚に単に
埋設、固定して使用される。以上から明らかなよ
うに、本発明生体端子は多様な形状・構造及び寸
法をとり得るものであつて特定形態に限定される
ものではない。 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 tube 7 such as a brass tube, and the average pore diameter is
It consists of a porous member 9 made of a 3μ alumina sintered body connected to the end, 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.
使用態様
前述の通り、本発明によりハイドロキシアパタ
イト焼結体等のアパタイト系材による生体端子は
生体適合性を有するのみならず表皮、真皮等の皮
膚組織と界面接合し生体に安定的に固定されるも
のであることが明らかにされたので、各種ドラツ
グ・デリバリシステムに於ける薬物投入口として
広汎な応用が可能であり、使用に当つては皮膚に
埋設、固定（インプラント）された生体端子に、
マイクロ・ポンプ等で定量的に駆動された薬液を
送入するチユーブ等を単に連絡すれば足りる。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 through which a chemical solution quantitatively driven by a micro pump or the like is fed.
ここで、本発明生体端子の特に有用な使用態様
として、薬物の駆動を電気化学的に行なう所謂イ
オントフオレーゼ（イオン導入療法）用注入口と
しての使用をあげ得る。 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.
例えば従来人工膵臓に於けるインスリン・HCl
の注入は、微量定量注入ポンプ（前掲医器学誌参
照）によりなされるものであつたが、これに代え
て本発明インプラント端子を単に直流電源の陽極
に電気的に連結するのみでインスリン・カチオン
は極めて容易且つ安全に生体内に導入され得るも
のとなる。 For example, insulin and HCl in conventional artificial pancreas
The injection of insulin was carried out using a micrometer injection pump (see the medical journal cited above), 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.
なぜなら、通常のイオントフオレーゼは皮膚上
から施術されるものであるが、その場合専ら皮膚
角質層が電気的並びに物理的バリヤ層となり、イ
ンスリン等の比較的大分子の導入は困難であつた
が、本発明生体端子に依れば皮膚角質層はもはや
バリヤとなり得ないのでインピーダンス及び物理
的抵抗の著るしい低下がもたされ、しかも電流値
（通常、インスリンの場合直流乃至パルス直流で
数μA〜数mAの範囲内）をコントロールするこ
とによりその定量的或いはグルコース・センサに
よるフイードバツク注入が容易に達成されるもの
である。 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 act as a barrier, resulting in a significant reduction in impedance and physical resistance, and the current value (usually, 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.
すなわち、本発明生体端子をイオントフオレー
ゼに使用する場合は、従来イオントフオレーゼに
於ける薬液含浸導子（一般にスポンジ、コツトン
等の保水材或いは親水性ゲル材より成る）に代え
て、インプラント生体端子に薬液注入導管を連結
して関導子とし、周知の各種生体電極（例えば、
特開昭58−10066又は特願昭56−106935号公報、
参照）より成る不関導子を皮膚の他の箇所に貼着
し、両者間に直流電流（イオン性薬剤がカチオン
ならば関導子陽極、等）を通ずれば足りるもので
ある。 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.).
尚、イオントフオレーゼ自体の詳細は前掲公報
の記載が参照される。 For details of the iontophorase itself, refer to the description in the above-mentioned publication.
以下、本発明を実験例により詳細に説明する。 Hereinafter, the present invention will be explained in detail using experimental examples.
実験例
１ 生体端子の製造
ハイドロキシアパタイト粉末は、0.5モル／
水酸カルシウムと0.3モル／リン酸溶液を
徐々に滴下し、37℃で１日反応させて合成し、
これを濾過乾燥して得た。この合成粉末を金型
に充填し、800Kg／cm2の圧力で圧縮成形し径２
mmの貫通孔を有し且つカサ密度1.6g／cm3の圧粉
体を得た。これを端子頭部形状（第１図参照）
に旋盤及び歯科用ダイヤモンドバーで切削、加
工した。同様に前記合成粉末を金型に充填圧縮
成形、切削加工して端子底部（第１図参照）と
した。次いで、両圧粉体の貫通孔を接合し、更
に両者間に予め水を加え乳鉢でよく練つたゲル
状アパタイト粉末を塗布し、接着した。これを
1250℃で１時間焼結処理して圧縮強度5000Kg／
cm2、曲げ強度1200Kg／cm2、相対密度95％且つ接
着部も均一に焼結した第１図に図示の通りの生
体端子を得た。Experimental example 1 Production of bioterminal Hydroxyapatite powder was 0.5 mol/
Calcium hydroxide and 0.3 mol/phosphoric acid solution were gradually added dropwise and reacted at 37°C for one 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 and a bulk density of 1.6 g/cm 3 . This is the terminal head shape (see Figure 1)
It was cut and processed 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
Sintered at 1250℃ for 1 hour to achieve compressive strength of 5000Kg/
cm 2 , bending strength of 1200 Kg/cm 2 , relative density of 95%, and the adhesive portion was uniformly sintered to obtain a bioterminal as shown in FIG. 1.
ここに於いて、端子底部は直径5.4mm、厚さ
２mm、端子頭部首部分の径は４mm及び内径２mm
である。 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.
尚、焼結温度を1100℃とした場合に得られる
焼結体にあつては、相対密度85％、圧縮強度
3000Kg／cm2、曲げ強度700Kg／cm2であつた。尚、
最終的に、合成樹脂筒体に配設された多孔性部
材（平均孔径4μのテフロン樹脂フイルム）を
第１図の様に端子内に装着して試供品とした。 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 porous member (Teflon resin film with an average pore diameter of 4 μm) arranged in a synthetic resin cylinder was installed inside the terminal as shown in Fig. 1 to prepare a sample.
２ 動物実験
上記生体端子を雑種成犬の側腹部皮膚に埋設
し、経時観察した結果、端子は底部及び首部分
に於いて術後約２週目で皮膚組織と強く結合接
着して引つ張つても取れない状態となり、１年
径過後でも肉眼的には炎症反応などの異常所見
は何ら認められなかつた。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 had passed, no abnormal findings such as inflammatory reactions were observed with the naked eye.
また、通常の組織学的検索でも炎症細胞など
は認められなかつた。 In addition, no inflammatory cells were found in normal histological examination.
他方、対照とした同形状のシリコーンゴム製
端子にあつては術後４週目でも皮膚との接着は
全然認められず既に炎症性の発赤が認められ
た。又、２ケ月目には炎症が進行し化膿し始
め、３ケ月目には脱落した。 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.
実験例
前記ハイドロキシアパタイト粉末に添加剤とし
てCa3（PO4）2 ７％、MgO 0.8％、Na2O 1.8％、
K2O 0.2％及びCaFe 0.2％を添加した混合粉末を
出発材料とした点を除き、他は前記例と同様にし
て径１mmの金管を含む小円柱状焼結材（外径３
mm）を製造し、これを研摩材で研摩処理して添付
第２図に図示する形状の微小管状端子を得た。Experimental example Ca 3 (PO 4 ) 2 7%, MgO 0.8%, Na 2 O 1.8%, as additives to the hydroxyapatite powder.
Except that the starting material was a mixed powder containing 0.2% K 2 O and 0.2% CaFe, a small cylindrical sintered material (outer 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.
この端子の焼結体部分の長さは８mm、外径２mm
であつた。 The length of the sintered part of this terminal is 8 mm, and the outer diameter is 2 mm.
It was hot.
次にこれに平均孔径50μのアルミナ焼結体製多
孔性部材を第２図のように連結した後、成犬胸部
にその先端が皮下に位置するように刺通埋設した
処、約３週後には皮膚組織と完全に接合、固定さ
れた状態となつた。 Next, a porous member made of alumina sintered body with an average pore diameter of 50μ was connected to this as shown in Figure 2, and then inserted into the chest of an adult dog so that the tip was located subcutaneously. was completely bonded and fixed to the skin tissue.
そこで、端子端部を生理食塩水の充填された導
管に接合し、直流抵抗を測定した結果（不関導子
としてはアドバンスエレクトロード社製心電図用
電極レクロードを他の剃毛胸部に貼着使用）、
3.8KΩの値が得られた。角質層を介した皮膚抵抗
が通常100KΩ程度であることと対比すると、抵
抗の著るしい低下が認められる。 Therefore, we connected the terminal end to a conduit filled with physiological saline and measured the DC resistance (as the indifferent conductor, we used an ECG electrode made by Advance Electrode attached to another shaved chest). ),
A value of 3.8KΩ was obtained. Compared to the normal skin resistance through the stratum corneum, which is about 100KΩ, a significant decrease in resistance is observed.
添付第１乃至２図は本発明生体端子の模式断面
図である。
，…薬物治療システム用生体端子、２…端
子頭部、３…端子底部、４，９…多孔性部材、
５，１０…筒体、６…貫通孔。
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, 9 ... porous member,
5, 10... Cylindrical body, 6... Through hole.
Claims (1)
ト系材より成り、且つ多孔性部材がその内部に設
けられた薬液導通路を備えていることを特徴とす
る経皮的薬物治療システム用生体端子。1. A bioterminal for a transdermal drug treatment system, characterized in that at least a portion in contact with skin tissue is made of an apatite-based material, and a porous member is provided with a drug fluid conduction path provided inside the porous member.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58166502A JPS6058154A (en) | 1983-09-12 | 1983-09-12 | Living body terminal for drug treating system |
| CA000450058A CA1247960A (en) | 1983-03-24 | 1984-03-21 | Transcutaneously implantable element |
| DE8484301977T DE3482893D1 (en) | 1983-03-24 | 1984-03-23 | ITEM FOR TRANSCUTANEOUS IMPLANTATION. |
| EP84301977A EP0120689B1 (en) | 1983-03-24 | 1984-03-23 | Transcutaneously implantable element |
| US07/577,820 US5035711A (en) | 1983-03-24 | 1990-09-05 | Transcutaneously implantable element |
| US07/581,122 US5026397A (en) | 1983-03-24 | 1990-09-10 | Transcutaneously implantable element |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58166502A JPS6058154A (en) | 1983-09-12 | 1983-09-12 | Living body terminal for drug treating system |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6058154A JPS6058154A (en) | 1985-04-04 |
| JPH0150416B2 true JPH0150416B2 (en) | 1989-10-30 |
Family
ID=15832544
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58166502A Granted JPS6058154A (en) | 1983-03-24 | 1983-09-12 | Living body terminal for drug treating system |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6058154A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62281954A (en) * | 1986-05-29 | 1987-12-07 | 京セラ株式会社 | Inside and outside opening member of living body |
| JPH0677602B2 (en) * | 1988-05-20 | 1994-10-05 | 旭光学工業株式会社 | Transdermal device |
-
1983
- 1983-09-12 JP JP58166502A patent/JPS6058154A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6058154A (en) | 1985-04-04 |
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