JPH04244013A - Calcium phosphate cement having sustained releasability of medicine - Google Patents
Calcium phosphate cement having sustained releasability of medicineInfo
- Publication number
- JPH04244013A JPH04244013A JP3029048A JP2904891A JPH04244013A JP H04244013 A JPH04244013 A JP H04244013A JP 3029048 A JP3029048 A JP 3029048A JP 2904891 A JP2904891 A JP 2904891A JP H04244013 A JPH04244013 A JP H04244013A
- Authority
- JP
- Japan
- Prior art keywords
- calcium phosphate
- medicine
- cement
- phosphate cement
- living body
- 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.)
- Granted
Links
- 239000004568 cement Substances 0.000 title claims abstract description 41
- 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 title claims abstract description 41
- 239000001506 calcium phosphate Substances 0.000 title claims abstract description 30
- 229910000389 calcium phosphate Inorganic materials 0.000 title claims abstract description 30
- 235000011010 calcium phosphates Nutrition 0.000 title claims abstract description 30
- 239000003814 drug Substances 0.000 title claims abstract description 30
- 230000002459 sustained effect Effects 0.000 title abstract 3
- 239000000843 powder Substances 0.000 claims abstract description 21
- 239000007788 liquid Substances 0.000 claims abstract description 12
- 239000011575 calcium Substances 0.000 claims abstract description 11
- 239000000203 mixture Substances 0.000 claims abstract description 11
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims abstract 3
- 229940079593 drug Drugs 0.000 claims description 23
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 10
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 claims description 10
- 238000013268 sustained release Methods 0.000 claims description 5
- 239000012730 sustained-release form Substances 0.000 claims description 5
- 238000002156 mixing Methods 0.000 abstract description 9
- 239000003795 chemical substances by application Substances 0.000 abstract description 8
- 210000000988 bone and bone Anatomy 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 5
- 239000002246 antineoplastic agent Substances 0.000 abstract description 3
- -1 antibiotic Substances 0.000 abstract description 2
- 230000003115 biocidal effect Effects 0.000 abstract description 2
- 108090000623 proteins and genes Proteins 0.000 abstract description 2
- 102000004169 proteins and genes Human genes 0.000 abstract description 2
- 230000000638 stimulation Effects 0.000 abstract 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 abstract 1
- 229910019142 PO4 Inorganic materials 0.000 abstract 1
- 229910052791 calcium Inorganic materials 0.000 abstract 1
- 230000001771 impaired effect Effects 0.000 abstract 1
- 239000002075 main ingredient Substances 0.000 abstract 1
- 238000012856 packing Methods 0.000 abstract 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 abstract 1
- 239000010452 phosphate Substances 0.000 abstract 1
- 238000013269 sustained drug release Methods 0.000 description 14
- XAAHAAMILDNBPS-UHFFFAOYSA-L calcium hydrogenphosphate dihydrate Chemical compound O.O.[Ca+2].OP([O-])([O-])=O XAAHAAMILDNBPS-UHFFFAOYSA-L 0.000 description 11
- 238000001356 surgical procedure Methods 0.000 description 5
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 4
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- FLKYBGKDCCEQQM-WYUVZMMLSA-M cefazolin sodium Chemical compound [Na+].S1C(C)=NN=C1SCC1=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 FLKYBGKDCCEQQM-WYUVZMMLSA-M 0.000 description 4
- 229960003408 cefazolin sodium Drugs 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- XMEVHPAGJVLHIG-FMZCEJRJSA-N chembl454950 Chemical compound [Cl-].C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H]([NH+](C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O XMEVHPAGJVLHIG-FMZCEJRJSA-N 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 238000002513 implantation Methods 0.000 description 3
- 230000007794 irritation Effects 0.000 description 3
- 229960004989 tetracycline hydrochloride Drugs 0.000 description 3
- PTNZGHXUZDHMIQ-UHFFFAOYSA-N 4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydrochloride Chemical compound Cl.C1=CC=C2C(C)C(C(O)C3C(C(O)=C(C(N)=O)C(=O)C3N(C)C)(O)C3=O)C3=C(O)C2=C1O PTNZGHXUZDHMIQ-UHFFFAOYSA-N 0.000 description 2
- 102000007350 Bone Morphogenetic Proteins Human genes 0.000 description 2
- 108010007726 Bone Morphogenetic Proteins Proteins 0.000 description 2
- 206010031252 Osteomyelitis Diseases 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 2
- 229940112869 bone morphogenetic protein Drugs 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- FWRNIJIOFYDBES-ZQDFAFASSA-L disodium;(2s,5r,6r)-3,3-dimethyl-7-oxo-6-[[(2r)-2-phenyl-2-sulfonatoacetyl]amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound [Na+].[Na+].C1([C@H](C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C([O-])=O)(C)C)S([O-])(=O)=O)=CC=CC=C1 FWRNIJIOFYDBES-ZQDFAFASSA-L 0.000 description 2
- 229960004082 doxycycline hydrochloride Drugs 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 229960003276 erythromycin Drugs 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- XJSFLOJWULLJQS-NGVXBBESSA-N josamycin Chemical compound CO[C@H]1[C@H](OC(C)=O)CC(=O)O[C@H](C)C\C=C\C=C\[C@H](O)[C@H](C)C[C@H](CC=O)[C@@H]1O[C@H]1[C@H](O)[C@@H](N(C)C)[C@H](O[C@@H]2O[C@@H](C)[C@H](OC(=O)CC(C)C)[C@](C)(O)C2)[C@@H](C)O1 XJSFLOJWULLJQS-NGVXBBESSA-N 0.000 description 2
- 229960004144 josamycin Drugs 0.000 description 2
- 238000004898 kneading Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 229960004857 mitomycin Drugs 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 229920002385 Sodium hyaluronate Polymers 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 150000001782 cephems Chemical class 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 229910010293 ceramic material Inorganic materials 0.000 description 1
- KXKPYJOVDUMHGS-OSRGNVMNSA-N chondroitin sulfate Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](OS(O)(=O)=O)[C@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](C(O)=O)O1 KXKPYJOVDUMHGS-OSRGNVMNSA-N 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 229940041009 monobactams Drugs 0.000 description 1
- 229910000392 octacalcium phosphate Inorganic materials 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 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 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229940010747 sodium hyaluronate Drugs 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229940074404 sodium succinate Drugs 0.000 description 1
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 description 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
- YIGWVOWKHUSYER-UHFFFAOYSA-F tetracalcium;hydrogen phosphate;diphosphate Chemical compound [Ca+2].[Ca+2].[Ca+2].[Ca+2].OP([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O YIGWVOWKHUSYER-UHFFFAOYSA-F 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Materials For Medical Uses (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Dental Preparations (AREA)
Abstract
Description
【０００１】0001
【産業上の利用分野】本発明はリン酸カルシウムセメン
トを基材とする薬物徐放性セメントに関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a sustained drug release cement based on calcium phosphate cement.
【０００２】0002
【従来の技術】従来、生体適合性の良い薬物徐放性材料
としては、例えば特開昭５９−１０１１４５号公報や特
開昭６０−１０６４５９号公報において、抗生剤や抗ガ
ン剤を多孔性のセラミックスと組合せたものが提案され
ている。しかしながら、前記薬物徐放性材料はいずれも
ある一定の形状を有するセラミックス材が基材であり、
術前又は術中に埋入部位に合わせて加工を施さなければ
ならないという問題がある。[Prior Art] Conventionally, as a drug sustained release material with good biocompatibility, for example, JP-A-59-101145 and JP-A-60-106459 disclose antibiotics and anticancer drugs in porous materials. A combination with ceramics has been proposed. However, all of the above-mentioned sustained drug release materials have a ceramic material having a certain shape as a base material,
There is a problem in that processing must be performed to suit the implantation site before or during surgery.
【０００３】一方、前記薬物徐放性材料として、リン酸
カルシウム系セメントが開発されている。前記リン酸カ
ルシウム系セメントは、術前又は術中に粉剤と液剤とを
混合し、ペースト状としたものを、埋入部位に注入放置
し、硬化させるので、非常に取り扱いが容易である。し
かしながら前記リン酸カルシウム系セメントの殆んどは
、例えば特開昭６０−２５３４５４号公報に開示される
ように、液剤としてかなり高濃度の酸を用いているため
、セメントの硬化が終了するまでは生体刺激が激しく、
また硬化後も未反応の酸の溶出によりｐＨが低下し、そ
の結果として生体に刺激を与え、更には薬効が低下する
などの問題がある。On the other hand, calcium phosphate cement has been developed as the drug sustained release material. The calcium phosphate cement is very easy to handle because it is made into a paste by mixing a powder and a liquid before or during surgery and is injected into the implantation site and left to harden. However, most of the above-mentioned calcium phosphate cements, as disclosed in JP-A No. 60-253454, use a fairly high concentration of acid as a liquid agent, so they do not cause biological irritation until the cement hardens. is intense,
Further, even after curing, the pH decreases due to the elution of unreacted acids, which causes irritation to living organisms and furthermore, there are problems such as a decrease in medicinal efficacy.
【０００４】0004
【発明が解決しようとする課題】本発明の目的は、生体
親和性に優れ、薬物をすべて放出した後も生体内から取
り出す必要が無く、また中性付近のｐＨで硬化するので
、生体刺激性が少なく、混合した薬物の薬効を損うこと
のない薬物徐放性リン酸カルシウムセメントを提供する
ことにある。[Problems to be Solved by the Invention] The objects of the present invention are to have excellent biocompatibility, eliminate the need to take out the drug from the body even after all the drug has been released, and cure at a pH around neutral, so that it has no bioirritating properties. An object of the present invention is to provide a calcium phosphate cement for sustained release of drugs, which has a small amount of oxidation and does not impair the efficacy of mixed drugs.
【０００５】本発明の別の目的は、操作性に優れ任意の
場所に充填することのできる薬物徐放性リン酸カルシウ
ムセメントを提供することにある。Another object of the present invention is to provide a sustained drug release calcium phosphate cement that has excellent operability and can be filled in any desired location.
【０００６】[0006]
【課題を解決するための手段】本発明によれば、粉剤と
液剤とから成り、且つ薬物を含有するリン酸カルシウム
セメントであって、該リン酸カルシウムセメントの粉剤
の主成分が、Ｃａ／Ｐモル比１．４０〜１．４９８とな
るように混合したα型第３リン酸カルシウムと第２リン
酸カルシウムとの混合物であることを特徴とする薬物徐
放性リン酸カルシウムセメントが提供される。[Means for Solving the Problems] According to the present invention, there is provided a calcium phosphate cement comprising a powder and a liquid and containing a drug, wherein the main component of the powder of the calcium phosphate cement has a Ca/P molar ratio of 1. Provided is a sustained drug release calcium phosphate cement, which is a mixture of α-type tertiary calcium phosphate and dibasic calcium phosphate, which are mixed to have a molecular weight of 40 to 1.498.
【０００７】以下本発明を詳細に説明する。The present invention will be explained in detail below.
【０００８】本発明の薬物徐放性リン酸カルシウムセメ
ントは、特定のＣａ／Ｐモル比を有するα型第３リン酸
カルシウムと第２リン酸カルシウムとの混合物を粉剤の
主成分とすることを特徴とする。The sustained drug release calcium phosphate cement of the present invention is characterized in that the main component of the powder is a mixture of α-type tertiary calcium phosphate and dibasic calcium phosphate having a specific Ca/P molar ratio.
【０００９】本発明の薬物徐放性リン酸カルシウムセメ
ントにおいて、粉剤の主成分として用いるα型第３リン
酸カルシウムと第２リン酸カルシウムとは、水の存在下
にて反応し、リン酸８カルシウムを生成し、硬化する成
分である。前記第２リン酸カルシウムとしては、市販の
第２リン酸カルシウム２水和物等を好ましく挙げること
ができる。また前記反応は、ｐＨ６〜８で最も速やかに
進行する。In the sustained drug release calcium phosphate cement of the present invention, α-type tertiary calcium phosphate and dibasic calcium phosphate used as the main components of the powder react in the presence of water to produce octacalcium phosphate and harden. It is an ingredient that Preferred examples of the second calcium phosphate include commercially available second calcium phosphate dihydrate. Further, the reaction proceeds most rapidly at pH 6 to 8.
【００１０】前記α型第３リン酸カルシウムと第２リン
酸カルシウムの混合割合は、Ｃａ／Ｐモル比で１．４０
〜１．４９８の範囲とする必要があり、更に強度をより
高くする為に、Ｃａ／Ｐモル比を１．４７〜１．４９５
とするのが好ましい。前記Ｃａ／Ｐモル比が１．４０未
満若しくは１．４９８を超える場合には、硬化体の強度
が低下するので前記範囲とする必要がある。[0010] The mixing ratio of the α-type tertiary calcium phosphate and dibasic calcium phosphate is 1.40 in Ca/P molar ratio.
It is necessary to set the Ca/P molar ratio to 1.47 to 1.498 in order to further increase the strength.
It is preferable that When the Ca/P molar ratio is less than 1.40 or more than 1.498, the strength of the cured product decreases, so it is necessary to keep it within the above range.
【００１１】また前記粉剤としては前記α型第３リン酸
カルシウム及び第２リン酸カルシウムのみで十分である
が、必要に応じて生体親和性に富むハイドロキシアパタ
イト、β型リン酸カルシウム、硫酸バリウム等のＸ線造
影剤等を添加して用いてもよい。[0011]Although it is sufficient to use only the α-type tertiary calcium phosphate and dibasic calcium phosphate as the powder, if necessary, X-ray contrast agents such as hydroxyapatite, β-type calcium phosphate, barium sulfate, etc., which are highly biocompatible, may be used. may be used by adding.
【００１２】本発明において用いる液剤としては、水の
みでも十分であるが、操作性をより向上させるために、
コンドロイチン硫酸ナトリウムやヒアルロン酸ナトリウ
ム等のムコ多糖類を、また硬化時間を短縮するためにコ
ハク酸ナトリウムや乳酸ナトリウム等の水溶性ナトリウ
ム塩類等を添加して用いてもよい。Although water alone is sufficient as the liquid agent used in the present invention, in order to further improve operability,
Mucopolysaccharides such as sodium chondroitin sulfate and sodium hyaluronate may be added, and water-soluble sodium salts such as sodium succinate and sodium lactate may be added to shorten the curing time.
【００１３】前記粉剤と液剤との配合割合は、重量比で
３００〜５０：１００の範囲とするのが好ましい。前記
粉剤の配合割合が５０未満の場合には、硬化に長時間を
要し、３００を超えると練和時の操作性が低下するので
好ましくない。[0013] The mixing ratio of the powder agent and the liquid agent is preferably in the range of 300 to 50:100 by weight. If the blending ratio of the powder agent is less than 50, it takes a long time to harden, and if it exceeds 300, the operability during kneading decreases, which is not preferable.
【００１４】本発明の薬物徐放性リン酸カルシウムセメ
ントにおいて使用する薬物としては、抗生剤、抗ガン剤
、骨形成因子（ＢＭＰ）等の特別の作用を有するタンパ
ク質等を好ましく挙げることができる。前記抗生剤は、
化学構造や活性の相違により、更にペニシリン系、セフ
ェム系、アミノグリコミド系、テトラサイクリン系、マ
クロライト系、モノバクタム系等に分類することができ
る。前記薬物を具体的に列挙すると、塩酸テトラサイク
リン、塩酸ドキシサイクリン、エリスロマイシン、ジョ
サマイシン、スルベニシリンナトリウム、セファゾリン
ナトリウム、マイトマイシンＣ等を好ましく挙げること
ができる。[0014] Preferred drugs used in the sustained drug release calcium phosphate cement of the present invention include antibiotics, anticancer drugs, and proteins with special effects such as bone morphogenetic protein (BMP). The antibiotic is
Based on differences in chemical structure and activity, they can be further classified into penicillins, cephems, aminoglycomides, tetracyclines, macrolytes, monobactams, etc. Preferred examples of the drugs include tetracycline hydrochloride, doxycycline hydrochloride, erythromycin, josamycin, sulbenicillin sodium, cefazolin sodium, and mitomycin C.
【００１５】前記薬物の配合割合は、使用する薬物の有
効濃度以上であって、充填される動物等に害を及ぼさな
い程度であれば特に限定されるものではない。[0015] The blending ratio of the drug is not particularly limited as long as it is at least the effective concentration of the drug used and does not harm the animals etc. to be filled.
【００１６】本発明の薬物徐放性リン酸カルシウムセメ
ントを調整する際のｐＨは、通常前記薬物の薬効が、ｐ
Ｈ６〜８の中性付近にて最も良く発揮され、酸性又はア
ルカリ性の環境下においては不安定となり急速に薬効を
失う（例えば、塩酸テトラサイクリンや塩酸ドキシサイ
クリンは、酸には強いがアルカリには弱く、またエリス
ロマイシンやジョサマイシンは酸に弱く、更には、スル
ベニシリンナトリウム、セファゾリンナトリウム、マイ
トマイシンＣ等は中性では安定ではあるが、酸性及びア
ルカリ性の環境下では不安定である）ので、また前記α
型第３リン酸カルシウムと第２リン酸カルシウムとの反
応が、ｐＨ６〜８で最も良く進行するので、ｐＨ６〜８
とするのが好ましい。[0016] The pH when adjusting the sustained drug release calcium phosphate cement of the present invention is usually determined so that the medicinal efficacy of the drug is
It exhibits its best properties near neutrality in H6-8, and becomes unstable in acidic or alkaline environments, rapidly losing its medicinal efficacy (for example, tetracycline hydrochloride and doxycycline hydrochloride are strong against acids but weak against alkalis; In addition, erythromycin and josamycin are sensitive to acids, and furthermore, sulbenicillin sodium, cefazolin sodium, mitomycin C, etc. are stable in neutral environments but unstable in acidic and alkaline environments).
The reaction between type tertiary calcium phosphate and dibasic calcium phosphate proceeds best at pH 6 to 8;
It is preferable that
【００１７】本発明の薬物徐放性リン酸カルシウムセメ
ントを調整するには、前記薬物が粉末状の場合には、前
記リン酸カルシウムセメントの粉剤に予め混合し、得ら
れた粉剤と液剤とを、また水に易溶な薬物、例えば塩酸
テトラサイクリンやセファゾリンナトリウム等を用いる
場合には、予め液剤に溶かして配合し、得られた液剤と
粉剤とをそれぞれ混合する等して得ることができる。To prepare the sustained drug release calcium phosphate cement of the present invention, when the drug is in powder form, it is mixed in advance with the powder of the calcium phosphate cement, and the resulting powder and liquid are mixed in water. When using easily soluble drugs such as tetracycline hydrochloride and cefazolin sodium, they can be obtained by dissolving and blending in a liquid preparation in advance, and mixing the resulting liquid preparation and powder, respectively.
【００１８】本発明の薬物徐放性リン酸カルシウムセメ
ントを使用するには、該粉剤及び液剤を練和したペース
ト若しくは硬化したセメントを埋入部位に充填すること
により使用することができる。この際、本発明の薬物徐
放性リン酸カルシウムセメントは、生体親和性の良いリ
ン酸カルシウムセメントを粉剤の主成分として用いてい
るので、薬効がなくなったと認められた後でも体内から
取り出す必要がない。The sustained drug release calcium phosphate cement of the present invention can be used by filling the implantation site with a paste made by kneading the powder and liquid or with hardened cement. In this case, since the sustained drug release calcium phosphate cement of the present invention uses calcium phosphate cement with good biocompatibility as the main component of the powder, there is no need to remove it from the body even after it is recognized that the drug has lost its efficacy.
【００１９】また本発明の薬物徐放性リン酸カルシウム
セメントの極めて有効な使用方法として、例えば人工関
節の置換手術に本発明の薬物徐放性リン酸カルシウムセ
メントを併用し、抗生剤等の薬物の放出により手術後の
感染を防止するとともに、本来の生体親和性に富む生体
用セメントとして、すなわち周囲に新生骨を誘導し、人
工関節と骨とを接合させる使用方法等が考えられる。[0019] Furthermore, as an extremely effective method of using the sustained drug release calcium phosphate cement of the present invention, for example, the sustained drug release calcium phosphate cement of the present invention may be used in conjunction with artificial joint replacement surgery, and the release of drugs such as antibiotics may be performed during surgery. In addition to preventing later infections, it can be used as a biological cement that is naturally biocompatible, that is, to induce new bone around it and join an artificial joint to bone.
【００２０】[0020]
【発明の効果】本発明の薬物徐放性リン酸カルシウムセ
メントは、生体親和性に富む特定組成のリン酸カルシウ
ムセメントを基材としているため、操作性に優れ、任意
の場所に充填することができ、また中性付近のｐＨで硬
化するので、薬物の薬効を損なう心配がなく、かつ生体
刺激性が低い。更には生体親和性に優れているので薬物
がすべて放出されたあとも、生体外に取り出す必要がな
く、薬物徐放性セメントとして有用である。Effects of the Invention The drug sustained release calcium phosphate cement of the present invention is based on a calcium phosphate cement with a specific composition that is highly biocompatible, so it has excellent operability and can be filled into any location. Since it hardens at a pH close to normal, there is no risk of impairing the efficacy of the drug, and it has low biological irritation. Furthermore, since it has excellent biocompatibility, there is no need to take it out of the body even after all the drug has been released, making it useful as a sustained drug release cement.
【００２１】[0021]
【実施例】以下、実施例及び比較例により本発明を更に
詳細に説明するが、本発明はこれらに限定されるもので
はない。EXAMPLES The present invention will be explained in more detail with reference to Examples and Comparative Examples, but the present invention is not limited thereto.
【００２２】[0022]
【参考例１】α型第３リン酸カルシウムと第２リン酸カ
ルシウム（和光純薬工業株式会社製；第２リン酸カルシ
ウム２水和物，特級）とをＣａ／Ｐモル比が１．４０、
１．４３、１．４６、１．４７、１．４９５、１．４９
８になるようにそれぞれ混合し、セメント粉剤を得た。
次いで得られた粉剤１００重量部と液剤として水６０重
量部とを、練和し、硬化させた。硬化時のセメントペー
ストのｐＨをリトマス試験紙を用いて測定したところ、
いずれもｐＨ６〜８の範囲内であった。また硬化時間及
び得られたセメント硬化体の圧縮強度を測定した。結果
を表１に示す。硬化時間はＪＩＳ Ｒ５２０１に準じ
、また圧縮強度は、セメント硬化体（７ｍｍφ，１４ｍ
ｍＬ）を人工体液に３日間浸漬した後、取り出して濡れ
た状態でインストロン社製万能試験機を使用して測定し
た。[Reference Example 1] α-type tribasic calcium phosphate and dibasic calcium phosphate (manufactured by Wako Pure Chemical Industries, Ltd.; dibasic calcium phosphate dihydrate, special grade) with a Ca/P molar ratio of 1.40,
1.43, 1.46, 1.47, 1.495, 1.49
They were mixed to obtain a cement powder. Next, 100 parts by weight of the obtained powder and 60 parts by weight of water as a liquid were kneaded and hardened. When the pH of the cement paste was measured using litmus paper during hardening,
In all cases, the pH was within the range of 6 to 8. In addition, the curing time and compressive strength of the obtained cement hardened body were measured. The results are shown in Table 1. The curing time is based on JIS R5201, and the compressive strength is as follows:
mL) was immersed in an artificial body fluid for 3 days, then taken out and measured in a wet state using an Instron universal testing machine.
【００２３】[0023]
【参考例２】α型第３リン酸カルシウムと第２リン酸カ
ルシウムとをＣａ／Ｐモル比１．３３及び１．４９９と
した以外は、参考例１と同様にして硬化時間と圧縮強度
を測定した。結果を表１に示す。[Reference Example 2] The curing time and compressive strength were measured in the same manner as in Reference Example 1, except that the Ca/P molar ratio of α-type tertiary calcium phosphate and dibasic calcium phosphate was 1.33 and 1.499. The results are shown in Table 1.
【００２４】[0024]
【表１】[Table 1]
【００２５】[0025]
【実施例１】α型第３リン酸カルシウムと第２リン酸カ
ルシウムとをＣａ／Ｐモル比が１．４８となるように混
合したセメント粉剤３ｇに、市販の注射用セファゾリン
ナトリウム水溶液（藤沢薬品工業株式会社製）を１．６
ｇ混合し、得られた混合物（以下セメント混合物Ａとい
う）を用いて、５ｍｍφ、３ｍｍＬの円盤を５個作製し
た。
得られた円盤を１００ｍｌの生理食塩水中に入れ、紫外
吸収法を用いて薬物の溶出状態を調べたところ、１日で
約５０重量％、３日で約７０重量％が溶出し、その後徐
々に減少し、２週間後にほぼすべて溶出した。つまり２
週間にわたって薬効が持続すると思われる。[Example 1] A commercially available aqueous solution of cefazolin sodium for injection (manufactured by Fujisawa Pharmaceutical Co., Ltd.) was added to 3 g of cement powder prepared by mixing α-type tertiary calcium phosphate and dibasic calcium phosphate so that the Ca/P molar ratio was 1.48. ) to 1.6
Using the resulting mixture (hereinafter referred to as cement mixture A), five disks each having a diameter of 5 mm and a length of 3 mm L were prepared. The obtained disk was placed in 100 ml of physiological saline and the elution state of the drug was examined using an ultraviolet absorption method. Approximately 50% by weight of the drug eluted in 1 day, about 70% by weight in 3 days, and then gradually The concentration decreased, and almost all of it was eluted after 2 weeks. In other words, 2
The medicinal effects are expected to last for weeks.
【００２６】[0026]
【実施例２】実施例１で調製したセメント混合物Ａを用
いて、最大径１〜２ｍｍφの顆粒状硬化体を作製した。
一方、犬の大腿骨に人工的に骨髄炎を生じさせ、皮質骨
を切除し、炎症部を掻爬した後、該欠損部に上記顆粒を
充填した。また前記セメント混合物Ａをペースト状のま
ま、同様の処置を施した他の犬の欠損部に注入し充填し
た。Example 2 Using the cement mixture A prepared in Example 1, hardened granules having a maximum diameter of 1 to 2 mmφ were prepared. On the other hand, osteomyelitis was artificially induced in the femur of a dog, the cortical bone was excised, the inflamed area was curetted, and the defect area was filled with the granules. Further, the cement mixture A was injected in paste form into the defect site of another dog that had undergone the same treatment to fill it.
【００２７】術後３ヶ月にて患部を切開して状態を確認
したが、３ケ月後にはいずれの場合も硬化したセメント
は多量の新生骨に取り囲まれており、骨の欠損は完全に
治癒しているのが認められた。また、いずれの場合にお
いても骨髄炎の再発は認められなかった。[0027] Three months after the surgery, the affected area was incised to check the condition, and after three months, the hardened cement was surrounded by a large amount of new bone, and the bone defect had completely healed. It was recognized that Furthermore, no recurrence of osteomyelitis was observed in any case.
Claims (1)
有するリン酸カルシウムセメントであって、該リン酸カ
ルシウムセメントの粉剤の主成分が、Ｃａ／Ｐモル比１
．４０〜１．４９８となるように混合したα型第３リン
酸カルシウムと第２リン酸カルシウムとの混合物である
ことを特徴とする薬物徐放性リン酸カルシウムセメント
。1. A calcium phosphate cement comprising a powder and a liquid and containing a drug, wherein the main component of the powder of the calcium phosphate cement has a Ca/P molar ratio of 1.
．． 1. A drug sustained release calcium phosphate cement, which is a mixture of α-type tertiary calcium phosphate and dibasic calcium phosphate, which are mixed to have a molecular weight of 40 to 1.498.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3029048A JP2927007B2 (en) | 1991-01-31 | 1991-01-31 | Drug sustained release calcium phosphate cement |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3029048A JP2927007B2 (en) | 1991-01-31 | 1991-01-31 | Drug sustained release calcium phosphate cement |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH04244013A true JPH04244013A (en) | 1992-09-01 |
| JP2927007B2 JP2927007B2 (en) | 1999-07-28 |
Family
ID=12265503
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3029048A Expired - Fee Related JP2927007B2 (en) | 1991-01-31 | 1991-01-31 | Drug sustained release calcium phosphate cement |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2927007B2 (en) |
-
1991
- 1991-01-31 JP JP3029048A patent/JP2927007B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JP2927007B2 (en) | 1999-07-28 |
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