JPS6326726B2 - - Google Patents
Info
- Publication number
- JPS6326726B2 JPS6326726B2 JP55078845A JP7884580A JPS6326726B2 JP S6326726 B2 JPS6326726 B2 JP S6326726B2 JP 55078845 A JP55078845 A JP 55078845A JP 7884580 A JP7884580 A JP 7884580A JP S6326726 B2 JPS6326726 B2 JP S6326726B2
- Authority
- JP
- Japan
- Prior art keywords
- salts
- water
- sodium
- compound
- soluble compound
- 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
- 150000001875 compounds Chemical class 0.000 claims description 33
- 239000000919 ceramic Substances 0.000 claims description 25
- 239000011148 porous material Substances 0.000 claims description 12
- 230000000144 pharmacologic effect Effects 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 4
- 239000003509 long acting drug Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000003814 drug Substances 0.000 description 22
- 150000003839 salts Chemical class 0.000 description 19
- 229940079593 drug Drugs 0.000 description 10
- 238000000034 method Methods 0.000 description 7
- 239000002639 bone cement Substances 0.000 description 6
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 229940088710 antibiotic agent Drugs 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 238000006116 polymerization reaction Methods 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 229960005322 streptomycin Drugs 0.000 description 3
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 229960004909 aminosalicylic acid Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229960001139 cefazolin Drugs 0.000 description 2
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 2
- 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 2
- 229960003408 cefazolin sodium Drugs 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 229940083542 sodium Drugs 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- SPCKHVPPRJWQRZ-UHFFFAOYSA-N 2-benzhydryloxy-n,n-dimethylethanamine;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 SPCKHVPPRJWQRZ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 239000002647 aminoglycoside antibiotic agent Substances 0.000 description 1
- KLOHDWPABZXLGI-YWUHCJSESA-M ampicillin sodium Chemical compound [Na+].C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C([O-])=O)(C)C)=CC=CC=C1 KLOHDWPABZXLGI-YWUHCJSESA-M 0.000 description 1
- 229960001931 ampicillin sodium Drugs 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 229910052586 apatite Inorganic materials 0.000 description 1
- 125000000637 arginyl group Chemical class N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 159000000009 barium salts Chemical class 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical class C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- IYNDLOXRXUOGIU-LQDWTQKMSA-M benzylpenicillin potassium Chemical compound [K+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1 IYNDLOXRXUOGIU-LQDWTQKMSA-M 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 229960003669 carbenicillin Drugs 0.000 description 1
- RTYJTGSCYUUYAL-YCAHSCEMSA-L carbenicillin disodium Chemical compound [Na+].[Na+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)C(C([O-])=O)C1=CC=CC=C1 RTYJTGSCYUUYAL-YCAHSCEMSA-L 0.000 description 1
- 229960000603 cefalotin Drugs 0.000 description 1
- 229960004366 ceftezole Drugs 0.000 description 1
- DZMVCVMFETWNIU-LDYMZIIASA-N ceftezole Chemical compound O=C([C@@H](NC(=O)CN1N=NN=C1)[C@H]1SC2)N1C(C(=O)O)=C2CSC1=NN=CS1 DZMVCVMFETWNIU-LDYMZIIASA-N 0.000 description 1
- ADLFUPFRVXCDMO-LIGXYSTNSA-M ceftizoxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=CCS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 ADLFUPFRVXCDMO-LIGXYSTNSA-M 0.000 description 1
- 229960000636 ceftizoxime sodium Drugs 0.000 description 1
- 239000004568 cement Substances 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- VUFGUVLLDPOSBC-XRZFDKQNSA-M cephalothin sodium Chemical compound [Na+].N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C([O-])=O)C(=O)CC1=CC=CS1 VUFGUVLLDPOSBC-XRZFDKQNSA-M 0.000 description 1
- SCLZRKVZRBKZCR-SLINCCQESA-M cloxacillin sodium Chemical compound [Na+].N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C([O-])=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl SCLZRKVZRBKZCR-SLINCCQESA-M 0.000 description 1
- 229960003026 cloxacillin sodium Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229960004060 dicloxacillin sodium Drugs 0.000 description 1
- SIGZQNJITOWQEF-VICXVTCVSA-M dicloxacillin sodium monohydrate Chemical compound O.[Na+].N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C([O-])=O)=O)C(=O)C1=C(C)ON=C1C1=C(Cl)C=CC=C1Cl SIGZQNJITOWQEF-VICXVTCVSA-M 0.000 description 1
- 150000005332 diethylamines Chemical class 0.000 description 1
- 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 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 229960004273 floxacillin Drugs 0.000 description 1
- PARMJFIQRZRMHG-VICXVTCVSA-M flucloxacillin sodium monohydrate Chemical compound O.[Na+].N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C([O-])=O)=O)C(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl PARMJFIQRZRMHG-VICXVTCVSA-M 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229960003884 hetacillin Drugs 0.000 description 1
- DXVUYOAEDJXBPY-NFFDBFGFSA-N hetacillin Chemical compound C1([C@@H]2C(=O)N(C(N2)(C)C)[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 DXVUYOAEDJXBPY-NFFDBFGFSA-N 0.000 description 1
- 125000000487 histidyl group Chemical class [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- MGFZNWDWOKASQZ-UMLIZJHQSA-M methicillin sodium Chemical compound [Na+].COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 MGFZNWDWOKASQZ-UMLIZJHQSA-M 0.000 description 1
- 229940019826 methicillin sodium Drugs 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229960003994 oxacillin sodium Drugs 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
- 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 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000002685 polymerization catalyst Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- VDUVBBMAXXHEQP-ZTRPPZFVSA-M sodium;(2s,6r)-3,3-dimethyl-6-[(5-methyl-3-phenyl-1,2-oxazole-4-carbonyl)amino]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound [Na+].N([C@@H]1C(N2[C@H](C(C)(C)SC21)C([O-])=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1 VDUVBBMAXXHEQP-ZTRPPZFVSA-M 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 229940072172 tetracycline antibiotic Drugs 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Description
【発明の詳細な説明】
この発明は続効性薬剤の製造法に関するもので
あり、さらに詳しくは薬理活性を有する水溶性の
化合物を多孔質セラミツクの小孔に充填したの
ち、それ自体公知の化学的手段により該水溶性化
合物を難溶性の化合物に変換することからなる続
効性薬剤の製造法に関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a long-acting drug, and more specifically, after filling the small pores of porous ceramic with a water-soluble compound having pharmacological activity, The present invention relates to a method for producing a long-acting drug, which comprises converting the water-soluble compound into a poorly soluble compound by technical means.
医薬品の薬効を長期間に亘つて持続させる薬剤
として、医薬を重合用モノマーに混合して重合さ
せた医薬混入重合体、いわゆる医薬混入骨セメン
トが開発され、実用に供されている。しかしなが
ら、この骨セメントは重合反応により製造される
ため、例えば熱に不安定な医薬品に適用できない
ばかりでなく、医薬品の混入割合にも限度がある
上、セメント内部に封じ込まれた医薬品は溶出せ
ず有効に利用されないという欠陥があつた。その
上、医薬の骨セメントからの溶出速度を制御し難
く、さらに骨セメントを長期間体内に埋入する場
合には重合用モノマーや重合用触媒等の溶出も懸
念されるなど、多くの問題点があつた。 BACKGROUND OF THE INVENTION As a drug that maintains the efficacy of pharmaceuticals over a long period of time, a drug-containing polymer, which is a polymerization of a drug mixed with a polymerization monomer, a so-called drug-containing bone cement, has been developed and put into practical use. However, since this bone cement is manufactured through a polymerization reaction, it is not only inapplicable to, for example, heat-unstable pharmaceuticals, but also has a limit to the proportion of pharmaceuticals that can be mixed in, and the pharmaceuticals sealed inside the cement cannot be eluted. The problem was that it was not used effectively. Furthermore, it is difficult to control the elution rate of pharmaceuticals from bone cement, and there are also concerns about the elution of polymerization monomers and polymerization catalysts when bone cement is implanted into the body for a long period of time. It was hot.
この発明の発明者らは、生体に対する為害性が
なく、かつ生体との親和性に優れた多孔質セラミ
ツクを担体として用い、その微細な小孔に医薬を
担持させれば、医薬品の薬効を長期間にわたつて
持続させ得るばかりでなく、骨セメントの有する
上記のような問題点を解消できることを先に見出
した。すなわち、多孔質セラミツクを担体とする
ことにより従来の骨セメントにみられたような非
医薬成分の体内への溶出のおそれがなくなると共
に、担体の小孔の孔径や小孔の割合、すなわち気
孔率を変化させることによつて、医薬の充填量や
溶出率、溶出速度を適宜調節することが可能とな
つた。 The inventors of this invention have discovered that by using porous ceramic as a carrier, which is not harmful to living organisms and has excellent affinity with living organisms, and by allowing pharmaceuticals to be supported in its fine pores, the efficacy of pharmaceuticals can be extended. It has previously been discovered that not only can it be sustained over a long period of time, but also the above-mentioned problems of bone cement can be solved. In other words, by using porous ceramic as a carrier, there is no risk of non-medicinal components leaching into the body, which is the case with conventional bone cement, and the pore size and proportion of the small pores of the carrier, that is, the porosity, is reduced. By changing the amount, it has become possible to adjust the filling amount, elution rate, and elution rate of the drug as appropriate.
この発明の発明者らは、薬効の持続時間をさら
に長期化するには、水に対する溶解性の低い医薬
を多孔質セラミツクに充填すればよい点に着目し
たが、水溶液に多孔質セラミツクを減圧下に浸漬
したのち乾燥するだけで充填できる水溶性医薬の
場合と異なつて、水に難溶性の医薬の場合には多
孔質セラミツクを医薬の懸濁液中に浸漬すること
となり、満足し得る量の医薬を充填するのが困難
であつた。そこで、さらに研究を重ねた結果、水
溶性の化合物を多孔質セラミツクの小孔に充填し
たのち、セラミツク中の該水溶性化合物を化学的
手段により難溶性化合物に変換させれば、水に難
溶性の医薬のセラミツクへの充填量を高め得るこ
とを見出し、この発明を完成した。 The inventors of this invention focused on the fact that in order to further prolong the duration of medicinal efficacy, it would be sufficient to fill porous ceramic with a drug with low solubility in water. Unlike the case of water-soluble medicines, which can be filled by simply immersing them in water and drying them, in the case of medicines that are poorly soluble in water, porous ceramics must be immersed in a suspension of the medicine, and a satisfactory amount of the medicine can be filled. It was difficult to fill the medicine. Therefore, as a result of further research, we found that if a water-soluble compound is filled into the small pores of porous ceramic and then the water-soluble compound in the ceramic is converted into a poorly soluble compound by chemical means, it will be difficult to dissolve in water. They discovered that it is possible to increase the amount of medicine filled into ceramics, and completed this invention.
この発明の方法は、薬理活性を有する水溶性の
化合物を多孔質セラミツクの小孔に充填したの
ち、該水溶性化合物をそれ自体公知の化学的手段
により難溶性化合物に変換することにより行われ
る。 The method of the present invention is carried out by filling the small pores of porous ceramic with a water-soluble compound having pharmacological activity, and then converting the water-soluble compound into a sparingly soluble compound by chemical means known per se.
薬理活性を有する水溶性の化合物としては、長
期間に亘りその薬効の持続を要求されるような医
薬、例えば抗生物質、抗がん剤、免疫能増強剤、
ホルモン剤等が例示される。そして、抗生物質と
してはセフアゾリンナトリウム、セフテゾールナ
トリウム、セフチゾキシムナトリウム、セフアロ
チンナトリウム等のセフアロスポリン系抗生物
質、アンピシリンナトリウム、カルベニシリンナ
トリウム、スルベニシリンナトリウム、カリンダ
シリンナトリウム、ヘタシリンカリウム、クロキ
サシリンナトリウム、カルフエシリンナトリウ
ム、フルクロキサシリンナトリウム、ベンジルペ
ニシリンカリウム、オキサシリンナトリウム、ジ
クロキサシリンナトリウム、メチシリンナトリウ
ム等のペニシリン系抗生物質のほかアミノグリコ
シド系抗生物質、マクロライド系抗生物質、テト
ラサイクリン系抗生物質などが例示される。 Examples of water-soluble compounds with pharmacological activity include drugs that require sustained efficacy over a long period of time, such as antibiotics, anticancer drugs, immune enhancers,
Examples include hormones and the like. Antibiotics include cephalosporin antibiotics such as cefazolin sodium, ceftezol sodium, ceftizoxime sodium, and cephalothin sodium, ampicillin sodium, carbenicillin sodium, sulbenicillin sodium, calindacillin sodium, and hetacillin. Penicillin antibiotics such as potassium, cloxacillin sodium, calfecillin sodium, flucloxacillin sodium, benzylpenicillin potassium, oxacillin sodium, dicloxacillin sodium, and methicillin sodium, as well as aminoglycoside antibiotics and macrolide antibiotics. , tetracycline antibiotics, and the like.
この発明の方法が適用されるのはこれらに限定
されるものでなく、遊離の化合物がその塩基もし
くは酸との塩に比してより難溶性である場合、な
らびに錯化合物や難溶性塩あるいは溶媒和化合物
とすることにより水に対する溶解度が低下するよ
うな場合のすべてにこの発明の方法が適用され得
る。 The method of the present invention is not limited to these cases, and is applicable to cases where the free compound is more poorly soluble than its salt with a base or acid, and when a complex compound, a poorly soluble salt, or a solvent is used. The method of the present invention can be applied to all cases where the solubility in water is reduced by forming a compound.
なお、上記において、塩基との塩としてはナト
リウム塩、カリウム塩、カルシウム塩、バリウム
塩等の無機塩基との塩、トリメチルアミン塩、ト
リエチルアミン塩、ジエチルアミン塩、トリエタ
ノールアミン塩、ピリジン塩、アニリン塩等の有
機塩基との塩、リジン塩、アルギニン塩、ヒスチ
ジン塩等の塩基性アミノ酸との塩などが例示さ
れ、酸との塩としては塩酸塩、臭化水素酸塩、硫
酸塩、硝酸塩等の無機酸との塩、Ｐ−トルエンス
ルホン酸塩、酒石酸塩、くえん酸塩、乳酸塩、酢
酸塩等の有機酸との塩、アスパラギン酸塩、グル
タミン酸塩等の酸性アミン酸との塩などが例示さ
れる。 In the above, salts with bases include salts with inorganic bases such as sodium salts, potassium salts, calcium salts, barium salts, trimethylamine salts, triethylamine salts, diethylamine salts, triethanolamine salts, pyridine salts, aniline salts, etc. Examples include salts with organic bases, salts with basic amino acids such as lysine salts, arginine salts, and histidine salts, and salts with acids such as inorganic salts such as hydrochlorides, hydrobromides, sulfates, and nitrates. Examples include salts with acids, salts with organic acids such as P-toluenesulfonate, tartrate, citrate, lactate, acetate, and salts with acidic amino acids such as aspartate and glutamate. Ru.
また、薬理活性を有する難溶性の錯化合物とし
ては、ストレプトマイシンCu2+、ストレプトマ
イシンNi2+、ストレプトマイシンCo2+、テトラ
サイクリンCa2+、パラアミノサリチル酸Cu2+、
パラアミノサリチル酸Co2+などが例示され、難
溶性塩としてはペニシリンのベネタミン塩、ベン
ザチン塩およびプロカイン塩、ジフエンヒドラミ
ンのタンニン酸塩などが例示される。 In addition, poorly soluble complex compounds with pharmacological activity include streptomycin Cu 2+ , streptomycin Ni 2+ , streptomycin Co 2+ , tetracycline Ca 2+ , para-aminosalicylic acid Cu 2+ ,
Para-aminosalicylic acid Co 2+ is exemplified, and poorly soluble salts include penicillin benetamine salt, benzathine salt, and procaine salt, diphenhydramine tannate salt, and the like.
これらの水溶性化合物を充填すべきセラミツク
としては、アルミナセラミツク、アパタイトセラ
ミツク等が例示され、その小孔の平均孔径は約
100μ以下が好ましく、気孔率は20〜80％程度が
適当である。セラミツク自体の形状および大きさ
は、上記の平均孔径や気孔率と共に、その使用目
的に応じて適宜定められ得る。 Examples of ceramics to be filled with these water-soluble compounds include alumina ceramics, apatite ceramics, etc., and the average pore diameter of their small pores is approximately
The porosity is preferably 100μ or less, and the appropriate porosity is about 20 to 80%. The shape and size of the ceramic itself, as well as the above-mentioned average pore diameter and porosity, can be determined as appropriate depending on its intended use.
多孔質セラミツクに水溶性化合物を充填するに
は、該化合物の水溶液中に多孔質セラミツクを浸
漬したのち、該セラミツクを通風乾燥、減圧乾
燥、凍結乾燥等の手段により乾燥すればよいが、
水溶液中へにセラミツクの浸漬を減圧下に行え
ば、水溶性化合物の充填量を高められて好まし
い。 In order to fill porous ceramic with a water-soluble compound, the porous ceramic may be immersed in an aqueous solution of the compound and then dried by means such as ventilation drying, reduced pressure drying, freeze drying, etc.
It is preferable to immerse the ceramic in the aqueous solution under reduced pressure because the amount of water-soluble compound loaded can be increased.
多孔質セラミツクの小孔中に充填された水溶性
化合物の難溶性化合物への変換、すなわち塩から
遊離化合物の形成ならびに錯化合物、難溶性塩お
よび溶媒和化合物の形成は、それ自体公知の化学
的手段により行われる。 The conversion of water-soluble compounds filled into the small pores of porous ceramics into poorly soluble compounds, i.e. the formation of free compounds from salts and the formation of complexes, poorly soluble salts and solvates, can be carried out using chemical methods known per se. done by means.
すなわち、水溶性化合物が塩基との塩、例えば
ナトリウム塩である場合には酸、例えば塩酸で処
理し、水溶性化合物が酸との塩、例えば塩酸塩で
ある場合には塩基、例えば水酸化ナトリウム水溶
液で処理し、錯化合物を得るには錯化合物形成性
化合物との反応により、難溶性塩を得るにはその
ような塩を形成し得る化合物との造塩反応によ
り、また溶媒和化合物を得るには該溶媒で処理す
るなどの、それ自体公知の方法により行われる。 That is, when the water-soluble compound is a salt with a base, e.g. a sodium salt, it is treated with an acid, e.g. hydrochloric acid; when the water-soluble compound is a salt with an acid, e.g. a hydrochloride, it is treated with a base, e.g. sodium hydroxide. Treatment with an aqueous solution to obtain a complex compound by reaction with a complex-forming compound, to obtain a poorly soluble salt by a salt-forming reaction with a compound capable of forming such a salt, and to obtain a solvate. This is carried out by a method known per se, such as treatment with the solvent.
なお、水溶性化合物のセラミツクへの充填およ
び該化合物の難溶性化合物への変換をくり返して
行えば、難溶性化合物のセラミツクへの充填量を
さらに一層高めることができ望ましい。 Note that it is desirable to repeat the filling of the water-soluble compound into the ceramic and the conversion of the compound into the poorly soluble compound, since it is possible to further increase the amount of the poorly soluble compound filled into the ceramic.
この発明の方法によれば、水に難溶性の医薬の
セラミツクへの充填量を高めることができる。し
たがつて、かかるセラミツクを筋肉中または骨髄
中に埋入したり、骨腫瘍などで患部を切除した骨
欠損部に充填したり、あるいは内服したりして用
いると、医薬成分のセラミツクからの溶出期間、
すなわち薬効の持続時間を著しく長期化すること
ができる。 According to the method of the present invention, it is possible to increase the amount of a poorly water-soluble medicine loaded into ceramic. Therefore, when such ceramics are implanted into muscles or bone marrow, filled into bone defects resulting from removal of affected areas such as bone tumors, or taken internally, pharmaceutical ingredients may elute from the ceramics. period,
In other words, the duration of drug efficacy can be significantly prolonged.
次に、この発明の方法を実施例により説明す
る。 Next, the method of the present invention will be explained using examples.
実施例 １
球状の多孔質セラミツク（直径５mm、平均孔径
約40μ、気孔率39％）をセフアゾリンナトリウム
の水溶液（20W／Ｖ％）中に減圧下に約５分間浸
漬したのち、真空乾燥する。これを次いで1N塩
酸中に減圧下に約５分間浸漬したのち、再び真空
乾燥する。上記の操作を３回くり返して得られた
セラミツク中のセフアゾリン充填量は11.2mg力価
であつた。Example 1 A spherical porous ceramic (diameter 5 mm, average pore size approximately 40 μ, porosity 39%) was immersed in an aqueous solution of cefazolin sodium (20 W/V%) for approximately 5 minutes under reduced pressure, and then vacuum dried. . This was then immersed in 1N hydrochloric acid under reduced pressure for about 5 minutes, and then vacuum-dried again. The amount of cefazolin loaded in the ceramic obtained by repeating the above operation three times was 11.2 mg titer.
これについて、生理食塩水（37℃、PH6.0）中
で溶出試験を行つたところ、20日間に亘つてセフ
アゾリンの溶出が持続した。 Regarding this, when a dissolution test was conducted in physiological saline (37°C, PH6.0), the dissolution of cefazolin continued for 20 days.
Claims (1)
ラミツクの小孔に充填したのち、それ自体公知の
化学的手段により該水溶性化合物を難溶性の化合
物に変換することを特徴とする続効性薬剤の製造
法。1. A long-acting drug characterized by filling the small pores of porous ceramic with a water-soluble compound having pharmacological activity, and then converting the water-soluble compound into a sparingly soluble compound by chemical means known per se. manufacturing method.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7884580A JPS574915A (en) | 1980-06-10 | 1980-06-10 | Preparation of medical preparation with long-lasting activity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7884580A JPS574915A (en) | 1980-06-10 | 1980-06-10 | Preparation of medical preparation with long-lasting activity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS574915A JPS574915A (en) | 1982-01-11 |
| JPS6326726B2 true JPS6326726B2 (en) | 1988-05-31 |
Family
ID=13673156
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7884580A Granted JPS574915A (en) | 1980-06-10 | 1980-06-10 | Preparation of medical preparation with long-lasting activity |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS574915A (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59101145A (en) * | 1982-11-30 | 1984-06-11 | 日本特殊陶業株式会社 | Chemical liquid impregnated porous ceramic |
| JPS6021763A (en) * | 1983-07-15 | 1985-02-04 | ティーディーケイ株式会社 | Artificial bone material |
| JPS60106459A (en) * | 1983-11-15 | 1985-06-11 | 三菱マテリアル株式会社 | Calcium phosphate filler |
| JPH0653153B2 (en) * | 1985-08-21 | 1994-07-20 | ティーディーケイ株式会社 | Method for storing and treating porous artificial bone material |
| GB8813033D0 (en) * | 1988-06-02 | 1988-07-06 | Geistlich Soehne Ag | Chemical compound |
| JPH04504103A (en) * | 1988-07-01 | 1992-07-23 | ファルマシア・アンド・アップジョン・カンパニー | Controlled release of antibiotic salts from implanted tablets |
| AU628419B2 (en) * | 1988-10-26 | 1992-09-17 | Hisamitsu Pharmaceutical Co. Ltd. | Interface for electric endermism |
| JPH0930988A (en) * | 1995-07-21 | 1997-02-04 | Sumitomo Osaka Cement Co Ltd | Sustained release porous ceramic molding for medicine and its production |
| US20040180091A1 (en) * | 2003-03-13 | 2004-09-16 | Chang-Yi Lin | Carbonated hydroxyapatite-based microspherical composites for biomedical uses |
| WO2014062839A1 (en) | 2012-10-16 | 2014-04-24 | Surmodics, Inc. | Wound packing device and methods |
| US10201457B2 (en) | 2014-08-01 | 2019-02-12 | Surmodics, Inc. | Wound packing device with nanotextured surface |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS54163807A (en) * | 1978-02-20 | 1979-12-26 | Battelle Institut E V | Implantable medical depo and production |
-
1980
- 1980-06-10 JP JP7884580A patent/JPS574915A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS54163807A (en) * | 1978-02-20 | 1979-12-26 | Battelle Institut E V | Implantable medical depo and production |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS574915A (en) | 1982-01-11 |
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