JP2008044960A - Solid drug for oral use - Google Patents
Solid drug for oral use Download PDFInfo
- Publication number
- JP2008044960A JP2008044960A JP2007253411A JP2007253411A JP2008044960A JP 2008044960 A JP2008044960 A JP 2008044960A JP 2007253411 A JP2007253411 A JP 2007253411A JP 2007253411 A JP2007253411 A JP 2007253411A JP 2008044960 A JP2008044960 A JP 2008044960A
- Authority
- JP
- Japan
- Prior art keywords
- test
- dissolution
- minutes
- tablet
- tablet according
- 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
- 239000003814 drug Substances 0.000 title abstract description 33
- 239000007787 solid Substances 0.000 title abstract description 19
- 229940079593 drug Drugs 0.000 title abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 55
- 238000004090 dissolution Methods 0.000 claims abstract description 48
- 239000004480 active ingredient Substances 0.000 claims abstract description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 38
- 238000007922 dissolution test Methods 0.000 claims abstract description 36
- 206010013990 dysuria Diseases 0.000 claims abstract description 21
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 56
- 239000000203 mixture Substances 0.000 claims description 47
- 239000000314 lubricant Substances 0.000 claims description 30
- 235000019359 magnesium stearate Nutrition 0.000 claims description 28
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 26
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 claims description 26
- 238000002156 mixing Methods 0.000 claims description 25
- 238000004519 manufacturing process Methods 0.000 claims description 23
- 239000012085 test solution Substances 0.000 claims description 23
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 22
- 208000028938 Urination disease Diseases 0.000 claims description 11
- 235000010355 mannitol Nutrition 0.000 claims description 11
- 239000011248 coating agent Substances 0.000 claims description 10
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 8
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 7
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 7
- 229920002261 Corn starch Polymers 0.000 claims description 6
- 239000011230 binding agent Substances 0.000 claims description 6
- 239000008120 corn starch Substances 0.000 claims description 6
- 210000003708 urethra Anatomy 0.000 claims description 6
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 5
- 208000004403 Prostatic Hyperplasia Diseases 0.000 claims description 5
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 5
- 230000002485 urinary effect Effects 0.000 claims description 5
- 208000000693 Neurogenic Urinary Bladder Diseases 0.000 claims description 4
- 206010029279 Neurogenic bladder Diseases 0.000 claims description 4
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 4
- 235000013539 calcium stearate Nutrition 0.000 claims description 4
- 239000008116 calcium stearate Substances 0.000 claims description 4
- 210000005036 nerve Anatomy 0.000 claims description 4
- 201000004240 prostatic hypertrophy Diseases 0.000 claims description 4
- 239000000454 talc Substances 0.000 claims description 4
- 229910052623 talc Inorganic materials 0.000 claims description 4
- 235000012222 talc Nutrition 0.000 claims description 4
- 238000010998 test method Methods 0.000 claims description 4
- 238000000576 coating method Methods 0.000 claims description 2
- 210000001635 urinary tract Anatomy 0.000 claims description 2
- 230000002159 abnormal effect Effects 0.000 claims 1
- 238000000748 compression moulding Methods 0.000 claims 1
- PNCPYILNMDWPEY-QGZVFWFLSA-N silodosin Chemical compound N([C@@H](CC=1C=C(C=2N(CCCO)CCC=2C=1)C(N)=O)C)CCOC1=CC=CC=C1OCC(F)(F)F PNCPYILNMDWPEY-QGZVFWFLSA-N 0.000 abstract description 60
- 150000003839 salts Chemical class 0.000 abstract description 17
- 239000012453 solvate Substances 0.000 abstract description 15
- -1 indoline compound Chemical class 0.000 abstract description 11
- 239000000651 prodrug Substances 0.000 abstract description 6
- 229940002612 prodrug Drugs 0.000 abstract description 6
- 230000000903 blocking effect Effects 0.000 abstract description 4
- 239000006186 oral dosage form Substances 0.000 abstract 1
- 239000002775 capsule Substances 0.000 description 56
- 238000002360 preparation method Methods 0.000 description 42
- 238000012360 testing method Methods 0.000 description 40
- 238000010828 elution Methods 0.000 description 29
- 238000009472 formulation Methods 0.000 description 28
- 229940126589 solid medicine Drugs 0.000 description 20
- 239000000126 substance Substances 0.000 description 20
- 239000000546 pharmaceutical excipient Substances 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- 238000005259 measurement Methods 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 230000000694 effects Effects 0.000 description 15
- 238000011049 filling Methods 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 13
- 239000000654 additive Substances 0.000 description 13
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 230000008859 change Effects 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- 239000008187 granular material Substances 0.000 description 11
- 239000012488 sample solution Substances 0.000 description 11
- 229920002472 Starch Polymers 0.000 description 9
- 239000008107 starch Substances 0.000 description 9
- 235000019698 starch Nutrition 0.000 description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 238000003860 storage Methods 0.000 description 8
- 230000000996 additive effect Effects 0.000 description 7
- 239000012086 standard solution Substances 0.000 description 7
- 229940124597 therapeutic agent Drugs 0.000 description 7
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- 239000008101 lactose Substances 0.000 description 6
- 229920000881 Modified starch Polymers 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 238000012790 confirmation Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 230000006872 improvement Effects 0.000 description 5
- 238000004806 packaging method and process Methods 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 230000005856 abnormality Effects 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000002845 discoloration Methods 0.000 description 4
- 239000007884 disintegrant Substances 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- OOSZCNKVJAVHJI-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]piperazine Chemical compound C1=CC(F)=CC=C1CN1CCNCC1 OOSZCNKVJAVHJI-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229940121363 anti-inflammatory agent Drugs 0.000 description 3
- 239000002260 anti-inflammatory agent Substances 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000000812 cholinergic antagonist Substances 0.000 description 3
- 208000013507 chronic prostatitis Diseases 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 229920001451 polypropylene glycol Polymers 0.000 description 3
- 201000007094 prostatitis Diseases 0.000 description 3
- 229940074545 sodium dihydrogen phosphate dihydrate Drugs 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 230000003068 static effect Effects 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- ZZIZZTHXZRDOFM-UHFFFAOYSA-N 2-(2-ethoxyphenoxy)ethyl-[1-(4-methoxy-3-sulfamoylphenyl)propan-2-yl]azanium;chloride Chemical compound Cl.CCOC1=CC=CC=C1OCCNC(C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 ZZIZZTHXZRDOFM-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 206010020853 Hypertonic bladder Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 208000034189 Sclerosis Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 2
- 208000026723 Urinary tract disease Diseases 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 230000001078 anti-cholinergic effect Effects 0.000 description 2
- 229940124599 anti-inflammatory drug Drugs 0.000 description 2
- 229940124350 antibacterial drug Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 229940105329 carboxymethylcellulose Drugs 0.000 description 2
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 230000005611 electricity Effects 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229960003511 macrogol Drugs 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 238000001782 photodegradation Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000010298 pulverizing process Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 229960003198 tamsulosin hydrochloride Drugs 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000001069 triethyl citrate Substances 0.000 description 2
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 2
- 235000013769 triethyl citrate Nutrition 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010005053 Bladder neck obstruction Diseases 0.000 description 1
- 206010049576 Bladder neck sclerosis Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- 206010063057 Cystitis noninfective Diseases 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
- 208000015824 Fowler syndrome Diseases 0.000 description 1
- 208000035381 Fowler urethral sphincter dysfunction syndrome Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 208000026602 Hinman syndrome Diseases 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
- 208000001089 Multiple system atrophy Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010031127 Orthostatic hypotension Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 206010037195 Psychogenic dysuria Diseases 0.000 description 1
- 208000029033 Spinal Cord disease Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010065584 Urethral stenosis Diseases 0.000 description 1
- 206010046477 Urethral syndrome Diseases 0.000 description 1
- 208000003800 Urinary Bladder Neck Obstruction Diseases 0.000 description 1
- 208000012931 Urologic disease Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 229960000250 adipic acid Drugs 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229960003103 alfuzosin hydrochloride Drugs 0.000 description 1
- YTNKWDJILNVLGX-UHFFFAOYSA-N alfuzosin hydrochloride Chemical compound [H+].[Cl-].N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(C)CCCNC(=O)C1CCCO1 YTNKWDJILNVLGX-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 230000002744 anti-aggregatory effect Effects 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000002981 blocking agent Substances 0.000 description 1
- 210000000692 cap cell Anatomy 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 201000003139 chronic cystitis Diseases 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- CSVGEMRSDNSWRF-UHFFFAOYSA-L disodium;dihydrogen phosphate Chemical compound [Na+].[Na+].OP(O)([O-])=O.OP(O)([O-])=O CSVGEMRSDNSWRF-UHFFFAOYSA-L 0.000 description 1
- 238000007786 electrostatic charging Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960002386 prazosin hydrochloride Drugs 0.000 description 1
- WFXFYZULCQKPIP-UHFFFAOYSA-N prazosin hydrochloride Chemical compound [H+].[Cl-].N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 WFXFYZULCQKPIP-UHFFFAOYSA-N 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 208000018591 proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome Diseases 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000012113 quantitative test Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000009475 tablet pressing Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 208000024722 urethra neoplasm Diseases 0.000 description 1
- 201000009160 urethral calculus Diseases 0.000 description 1
- 206010046459 urethral obstruction Diseases 0.000 description 1
- 201000001988 urethral stricture Diseases 0.000 description 1
- 208000014001 urinary system disease Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は排尿障害治療用経口固形医薬に関するものである。詳しくは、活性成分として、α１−アドレナリン受容体（以下、α１−ＡＲという）遮断作用を有する、式（I）：
を含有する排尿障害治療用医薬であって、日本薬局方溶出試験法第２法（パドル法）で、水を試験液とし、回転数を５０回／分とする溶出試験における８５％溶出時間が６０分以下である経口固形医薬に関するものである。
The present invention relates to an oral solid medicine for treating urination disorder. Specifically, as an active ingredient, α 1 -adrenergic receptor (hereinafter referred to as α 1 -AR) blocking action, which has the formula (I):
本発明はまた、活性成分として、ＫＭＤ−３２１３、そのプロドラッグ、若しくはそれらの薬理学的に許容される塩、またはそれらの薬理学的に許容される溶媒和物の他に、さらに、ＫＭＤ−３２１３以外のα１−アドレナリン受容体遮断薬、抗コリン薬、抗炎症薬および抗菌薬の群から選ばれる少なくとも１種を含有する排尿障害治療用医薬であって、日本薬局方溶出試験法第２法（パドル法）で、水を試験液とし、回転数を５０回／分とする溶出試験における８５％溶出時間が６０分以下である経口固形医薬に関するものである。 In addition to KMD-3213, a prodrug thereof, or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable solvate thereof, the present invention further includes KMD- A medicament for the treatment of dysuria containing at least one selected from the group consisting of α 1 -adrenergic receptor blockers, anticholinergic drugs, anti-inflammatory drugs and antibacterial drugs other than 3213, which is the Japanese Pharmacopoeia Dissolution Test Method 2 The present invention relates to an oral solid medicine having an 85% dissolution time of 60 minutes or less in a dissolution test in which a water is used as a test solution and a rotation speed is 50 times / minute.
本発明はさらに、活性成分としてＫＭＤ−３２１３、そのプロドラッグ、若しくはそれらの薬理学的に許容される塩、またはそれらの薬理学的に許容される溶媒和物を含有する排尿障害治療用医薬であって、日本薬局方溶出試験法第２法（パドル法）で、水を試験液とし、回転数を５０回／分とする溶出試験における８５％溶出時間が６０分以下であり、且つ、ＫＭＤ−３２１３以外のα１−アドレナリン受容体遮断薬、抗コリン薬、抗炎症薬および抗菌薬の群から選ばれる少なくとも１種を活性成分として含有する医薬とを組み合わせて使用できる経口固形医薬およびその組み合わせによりなるキット医薬に関するものである。 The present invention further relates to a medicament for treating urination disorder, which contains, as an active ingredient, KMD-3213, a prodrug thereof, or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable solvate thereof. According to Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method), 85% dissolution time in a dissolution test using water as a test solution and a rotation speed of 50 times / minute is 60 minutes or less, and KMD Oral solid medicine that can be used in combination with a medicine containing at least one selected from the group of α 1 -adrenergic receptor blockers, anticholinergic drugs, anti-inflammatory drugs and antibacterial drugs other than -3213, and combinations thereof It is related with the kit pharmaceutical consisting of.
本発明の排尿障害治療用経口固形医薬は、日本薬局方溶出試験法第２法（パドル法）で、水を試験液とし、回転数を５０回／分とする溶出試験における８５％溶出時間（以下、Ｔ８５％という）が６０分以下であればよいが、試験液を日本薬局方崩壊試験法試験液第１液（以下、第１液という）とし、回転数を５０回／分とする溶出試験におけるＴ８５％も６０分以下であることが望ましく、試験液を水または第１液とし、回転数を５０回／分とする溶出試験のいずれにおいても、Ｔ８５％が３０分以下であるものがより望ましく、Ｔ８５％が１５分以下であるものが最も望ましい。 The oral solid medicine for treatment of urination disorder according to the present invention is the Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method), with 85% dissolution time in a dissolution test using water as a test solution and a rotation speed of 50 times / minute ( (Hereinafter referred to as “T85%”) may be 60 minutes or less, but the test solution is the Japanese Pharmacopoeia Disintegration Test Method Test Solution No. 1 (hereinafter referred to as “No. 1 Solution”) and the number of revolutions is 50 times / min T85% in the test is desirably 60 minutes or less, and in any dissolution test in which the test solution is water or the first solution and the rotation speed is 50 times / minute, T85% is 30 minutes or less. More preferably, T85% is most preferably 15 minutes or less.
本発明の溶出試験において用いられる試験液の第１液とは、日本薬局方崩壊試験法の試験液第１液を意味し、塩化ナトリウム２．０ｇに塩酸７．０ｍｌおよび水を加えて１０００ｍｌにした試験液である。 The first liquid of the test liquid used in the dissolution test of the present invention means the first liquid of the test liquid of the Japanese Pharmacopoeia Disintegration Test Method, and 7.0 ml of hydrochloric acid and water are added to 2.0 g of sodium chloride to 1000 ml. The test solution.
本発明の排尿障害治療用経口固形医薬に活性成分として含有されるＫＭＤ−３２１３は、選択的な尿道平滑筋収縮抑制作用を有し、強力な血圧低下作用または起立性低血圧を惹起することのない排尿困難治療剤として極めて有用な化合物であることが知られている。 KMD-3213 contained as an active ingredient in the oral solid medicine for treatment of dysuria according to the present invention has a selective urethral smooth muscle contraction inhibitory action and induces a strong blood pressure lowering action or orthostatic hypotension. It is known that the compound is extremely useful as a therapeutic agent for dysuria.
これまで、ＫＭＤ−３２１３またはその薬理学的に許容される塩またはそれらの薬理学的に許容される溶媒和物を包含する当該化合物を活性成分として含有する医薬品組成物については、ＫＭＤ−３２１３を含む一般式で表されるインドリン化合物に関する特許出願明細書において、インドリン化合物全体を対象とした一般的な記載の中で、経口固形製剤の剤形が例示され、一般の製剤学的手法で調製できると記載されている（例えば、特許文献１参照）。 So far, for pharmaceutical compositions containing the compound as an active ingredient, including KMD-3213 or a pharmacologically acceptable salt thereof or a pharmacologically acceptable solvate thereof, KMD-3213 is used. In the patent application specification relating to the indoline compound represented by the general formula including, in the general description for the whole indoline compound, the dosage form of the oral solid preparation is exemplified and can be prepared by a general pharmaceutical method (For example, refer to Patent Document 1).
しかしながら、本特許文献１にはＫＭＤ−３２１３を有効成分として含む製剤に関する具体的な記載は全くなされていない。
However, this
また、ＫＭＤ−３２１３を含むα１−ＡＲ遮断薬を有効成分として含有する下部尿路症治療剤に関する特許出願明細書において、医薬品組成物に関する一般的な記載の中で、経口固形製剤の剤形が例示され、医薬品添加物の例示と共に、公知方法によって製造できると記載されている（例えば、特許文献２参照）。 Moreover, in the patent application specification regarding the therapeutic agent for lower urinary tract containing an α 1 -AR blocker containing KMD-3213 as an active ingredient, the dosage form of an oral solid preparation is described in the general description regarding the pharmaceutical composition. It is described that it can be produced by a known method together with examples of pharmaceutical additives (see, for example, Patent Document 2).
しかしながら、本特許文献２にも、ＫＭＤ−３２１３を活性成分として含有する医薬品組成物に関する具体的な記載は全くなされていない。
However, this
ＫＭＤ−３２１３は光に対して比較的不安定であり、また、医薬品添加物の種類によっては配合変化を起こして分解物を生じやすく、さらに、賦形剤として最も一般的な乳糖との相性も悪く、乳糖を使用した場合、良好な溶出特性が得られにくく、錠剤の硬度が低くなるなどの問題を有している。また、ＫＭＤ−３２１３は付着性が強く、錠剤またはカプセル剤の製造において滑沢剤が不可欠である一方で、この滑沢剤添加による溶出時間の遅延を生じやすいなどの問題を有している。従って、ＫＭＤ−３２１３若しくはその薬理学的に許容される塩、またはそれらの薬理学的に許容される溶媒和物を含有する経口固形医薬は、通常の製造方法によっては、実用に供されうる製剤を製造することが困難である。 KMD-3213 is relatively unstable with respect to light, and depending on the type of pharmaceutical additive, it tends to cause a degradation product due to a change in the composition, and further has compatibility with the most common lactose as an excipient. Unfortunately, when lactose is used, there are problems such that it is difficult to obtain good dissolution characteristics and the hardness of the tablet is lowered. KMD-3213 has strong adhesion, and a lubricant is indispensable in the production of tablets or capsules. However, KMD-3213 has a problem that elution time tends to be delayed due to the addition of the lubricant. Therefore, an oral solid pharmaceutical containing KMD-3213 or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable solvate thereof is a preparation that can be put to practical use depending on a normal production method. Is difficult to manufacture.
特許文献１および特許文献２にはこれらの問題点についても、それを解決する方法についても全く報告も示唆もされていない。また、特許文献２には、塩酸タムスロシンまたはアルフゾシン塩酸塩を有効成分として含有するカプセル剤の製造方法が記載されているが、本発明の医薬組成物とは組成を全く異にするものであり、当該製造方法では本発明の医薬を得ることはできず、さらに、当該発明に基づいて当業者が本発明を成すことができるものではない。
本発明の目的は、血圧に対する影響が少なく、排尿障害治療剤として極めて有用な、ＫＭＤ−３２１３、そのプロドラッグ、若しくはそれらの薬理学的に許容される塩、またはそれらの薬理学的に許容される溶媒和物を活性成分として含有する医薬であって、活性成分の含有量の精度がよく、安定でしかも溶出特性が優れた、実用的な経口固形医薬を提供することである。 An object of the present invention is to provide KMD-3213, a prodrug thereof, or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable salt thereof that has little effect on blood pressure and is extremely useful as a therapeutic agent for dysuria. The present invention is to provide a practical oral solid medicine which contains a solvate as an active ingredient, has a high accuracy of the content of the active ingredient, is stable and has excellent dissolution characteristics.
経口医薬では活性成分をいかに効率よく体内に吸収させるかが重要な問題になるが、一方で、常に一定の効果を発揮させることも重要である。このため、製造ロット間の均質性、すなわち、各製剤間で、生物学的同等性を確保することが求められる。薬局方には、一定水準の品質と生物学的同等性の管理基準として、固形製剤の崩壊性および溶出性の試験方法が規定されており、医薬品は、それらの試験に基づいて設定された規格に適合することが求められている。 In oral medicine, how to efficiently absorb the active ingredient into the body is an important issue, but on the other hand, it is also important to always exert a certain effect. For this reason, it is required to ensure homogeneity between production lots, that is, bioequivalence between each preparation. The pharmacopoeia stipulates test methods for the disintegration and dissolution properties of solid preparations as a standard for managing a certain level of quality and bioequivalence, and pharmaceuticals are standards set based on those tests. It is required to conform to.
最近では、溶出試験が有効性および安全性を予測する手段として重要視されるようになっており、特に難溶性薬剤では崩壊性よりも溶出性が意義のある品質特性と考えられている。 Recently, dissolution tests have come to be regarded as important as a means of predicting efficacy and safety. In particular, dissolution characteristics are considered to be more significant than disintegration quality characteristics for poorly soluble drugs.
溶出試験は、生物学的同等性確保の点からできるだけ多くの試験条件で行う方が望ましいが、現実には多くの条件下での規格設定は困難であるため、生物学的非同等性を最も捉えやすい試験条件で試験される。溶出試験の試験液としては、生理学的変動範囲のｐＨ試験液（ｐＨ１〜７）または水が用いられるが、通常、溶出速度が遅い、すなわち溶出性が悪い試験液の方が製剤間の差を検出しやすい。また、水はｐＨが変動しやすいという欠点をもつ一方で、処方、製法の差に鋭敏に反応しやすい試験液であり、水で試験できる場合はできるだけ水を使用することが、試験効率、経済性、環境面などから推奨されている。
Although it is desirable to conduct dissolution tests under as many test conditions as possible from the viewpoint of ensuring bioequivalence, in reality it is difficult to set standards under many conditions, so bioequivalence is the most important. Tested under easy-to-understand test conditions. As a test solution for dissolution test, a pH test solution (
ＫＭＤ−３２１３は酸性の液には比較的溶解性が高いが、中性の水には難溶であることから、水における溶出試験が最も生物学的非同等性を捉えやすい条件といえる。従って、ＫＭＤ−３２１３を有効成分として含有する経口固形製剤については、水における溶出特性が良好な製剤が求められる。本発明の医薬においては、日本薬局方溶出試験法第２法（パドル法）で、水を試験液とし、回転数を５０回／分とする溶出試験において少なくともＴ８５％が６０分以下であることが望ましく、Ｔ８５％が３０分以下であることがより望ましく、Ｔ８５％が１５分以下であることが最も望ましい。 KMD-3213 has a relatively high solubility in acidic liquids, but is hardly soluble in neutral water. Therefore, it can be said that the elution test in water is the most easy condition for capturing biological non-equivalence. Therefore, an oral solid preparation containing KMD-3213 as an active ingredient is required to have a good dissolution property in water. In the pharmaceutical of the present invention, at least T85% is 60 minutes or less in the dissolution test using the Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method) with water as the test solution and the rotation speed of 50 times / minute. More preferably, T85% is more preferably 30 minutes or less, and most preferably T85% is 15 minutes or less.
また、経口固形製剤の場合、酸に対して不安定であることなどにより腸溶性製剤が求められるなどの特別の場合を除き、胃内での溶出性が良好であることが望まれるが、ＫＭＤ−３２１３は酸に対して安定であるので、ＫＭＤ−３２１３を有効成分として含有する経口固形製剤については、胃液に相当する第１液における溶出試験においても良好であることが望ましい。具体的には、第１液における溶出試験においても、水における溶出試験と同様に、少なくともＴ８５％が６０分以下であることが望ましく、Ｔ８５％が３０分以下であることがより望ましく、Ｔ８５％が１５分以下であることが最も望ましい。 In addition, in the case of oral solid preparations, good dissolution in the stomach is desired except for special cases where enteric preparations are required due to acid instability, etc. Since −3213 is stable against acid, it is desirable that the oral solid preparation containing KMD-3213 as an active ingredient is good in the dissolution test in the first liquid corresponding to gastric juice. Specifically, in the dissolution test in the first liquid, similarly to the dissolution test in water, at least T85% is desirably 60 minutes or less, T85% is more desirably 30 minutes or less, and T85% Is most preferably 15 minutes or less.
医薬品において含有される活性成分は、一般的に、微量で強い作用効果を発揮するため、常に一定の効果を発揮させるためには、活性成分の含有量が一定であることは勿論のこと、保存における活性成分の含有量の低下を最小限に抑えることが重要であり、このために製剤ロット間での含有量のバラツキがなく、且つ、保存における安定性が高いことが求められる。 In general, active ingredients contained in pharmaceutical products exhibit a strong effect in a small amount. Therefore, in order to always exert a certain effect, the content of the active ingredient is of course constant. It is important to minimize the decrease in the content of the active ingredient in the preparation, and for this reason, it is required that the content does not vary between preparation lots and that the stability in storage is high.
本発明の経口固形医薬に活性成分として含有されるＫＭＤ−３２１３は付着性が強く、また静電気を帯びやすく、特に、乾式法で製造する場合、製剤製造における粉砕、攪拌混合、造粒等の操作における物理的刺激により容易に帯電して、粉砕物、混合物または造粒物の流動性が低くなり、操作性が悪く、しかも充填量がばらついて活性成分含有量の精度が低くなる等の問題を生じやすい。 KMD-3213 contained as an active ingredient in the oral solid medicine of the present invention has strong adhesiveness and is easily charged with static electricity. In particular, when it is produced by a dry method, operations such as pulverization, stirring and mixing in the preparation of the preparation are performed. Easily charged by physical stimulation, resulting in low fluidity of the pulverized product, mixture or granulated product, poor operability, and variation in filling amount, resulting in reduced accuracy of active ingredient content. Prone to occur.
また、カプセル剤および錠剤の場合、操作性や充填精度などの面から、充填工程または打錠工程において滑沢剤が添加される。特に本発明の経口固形医薬に活性成分として含有されるＫＭＤ−３２１３は付着性が強いため、滑沢剤の添加が必須であるが、この滑沢剤添加によっても溶出時間の遅延を生じる。 In the case of capsules and tablets, a lubricant is added in the filling step or tableting step from the viewpoint of operability and filling accuracy. In particular, since KMD-3213 contained as an active ingredient in the oral solid medicine of the present invention has strong adhesion, addition of a lubricant is essential. However, the addition of the lubricant also causes a delay in elution time.
さらに、本発明の経口固形医薬に活性成分として含有されるＫＭＤ−３２１３は光に対して比較的不安定なため取扱いに注意を要し、通常の製剤の場合、遮光包装での保存が必須であるが、不透明の遮光包装の場合、異物等の混入の判別が困難であり、さらに、実際に服用する患者は、遮光包装から取り出した状態で保管することも予想されるため、遮光包装の必要のない光安定性の高い製剤が望まれる。 Furthermore, KMD-3213 contained as an active ingredient in the oral solid medicine of the present invention is relatively unstable with respect to light and therefore needs to be handled with care. In the case of normal preparations, storage in light-shielding packaging is essential. However, in the case of opaque light-shielding packaging, it is difficult to discriminate foreign substances, and it is expected that patients who actually take it will be stored in a state where they are taken out of the light-shielding packaging. A highly light-stable preparation with no odor is desired.
本発明者らは、排尿障害治療剤として極めて有用な、ＫＭＤ−３２１３、そのプロドラッグ、若しくはそれらの薬理学的に許容される塩、またはそれらの薬理学的に許容される溶媒和物を活性成分として含有する薬剤であって、含有量の精度がよく、水、または水および第１液における溶出特性が優れ、しかも、安定性が高い、経口固形医薬を開発すべく鋭意研究を行った。 The present inventors activated KMD-3213, a prodrug thereof, or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable solvate thereof, which is extremely useful as a therapeutic agent for dysuria. Intensive research was conducted to develop an oral solid medicine which is a drug contained as a component and has a high content accuracy, excellent elution characteristics in water or water and the first liquid, and high stability.
その結果、賦形剤として一般的に用いられる乳糖は、溶出時間を遅延させる傾向があり、また、錠剤の硬度が低くなるなどの問題点が多く、賦形剤として乳糖を使用した場合、好適な製剤が得られにくいことを見出した。本発明者らは、賦形剤について鋭意検討を加えた結果、賦形剤としてＤ−マンニトールを使用することによって極めて良好な溶出特性が確保できることを見出した。 As a result, lactose generally used as an excipient tends to delay the dissolution time, and has many problems such as reduced tablet hardness, and is suitable when lactose is used as an excipient. It was found that a difficult formulation could not be obtained. As a result of intensive studies on excipients, the present inventors have found that extremely good dissolution characteristics can be secured by using D-mannitol as an excipient.
本発明者らは、さらに製剤の製造方法について検討を加え、湿式法により顆粒を調製し、滑沢剤の添加量と混合時間を調整することにより、静電気の帯電による充填量のばらつきを生じることなく、安定でしかも溶出特性の優れた製剤が得られること、特にカプセル剤の場合は、固形の親水性あるいは界面活性作用を示す添加剤と滑沢剤とを特定の比率で混合して添加することにより溶出特性の優れた製剤が得られること、さらに、製剤の光安定性について、ＫＭＤ−３２１３の光分解性に対して酸化チタンが極めて良好な防止効果を示し、酸化チタンを配合したカプセルまたは酸化チタンを配合したコーティング剤を用いることにより光安定性の高い製剤が得られること、等の知見を得、本発明を成すに至った。 The present inventors further examined the production method of the preparation, prepared granules by a wet method, and adjusted the addition amount of the lubricant and the mixing time, thereby causing variations in the filling amount due to electrostatic charging. A stable preparation with excellent dissolution characteristics, especially in the case of capsules, a solid hydrophilic or surface active additive and a lubricant are mixed at a specific ratio and added. In this way, it is possible to obtain a preparation with excellent dissolution characteristics, and further, regarding the light stability of the preparation, titanium oxide exhibits a very good preventive effect on the photodegradability of KMD-3213, or a capsule containing titanium oxide or The present inventors have obtained the knowledge that a highly light-stable preparation can be obtained by using a coating agent containing titanium oxide, and have achieved the present invention.
活性成分として含有される化合物は比較的不安定であることが多く、固形製剤の製造に使用される各種医薬品添加物の種類によっては相互作用を起こし、変色あるいは分解等を生じる可能性があるため、使用できる医薬品添加物に制限があるが、その適否を予測することは困難である。 Since compounds contained as active ingredients are often relatively unstable, they may interact and cause discoloration or decomposition depending on the type of various pharmaceutical additives used in the production of solid preparations. Although there are restrictions on the pharmaceutical additives that can be used, it is difficult to predict their suitability.
この事から先ず、本発明の医薬に活性成分として含有されるＫＭＤ−３２１３について、固形製剤の製造で使用される各種医薬品添加剤との相互作用について確認試験を行い、変色あるいは分解等を生じさせない医薬品添加剤を選別し、次いで、それらの組み合わせおよび製造上の適否についてさらに検討を行った。 From this, first, KMD-3213 contained as an active ingredient in the medicament of the present invention is subjected to a confirmation test for interaction with various pharmaceutical additives used in the production of solid preparations, and does not cause discoloration or decomposition. Pharmaceutical excipients were screened and then further examined for their combination and manufacturing suitability.
先ず賦形剤について検討した結果、最も一般的に用いられる乳糖は、配合変化は起こさないものの溶出特性を低下させる傾向があり、さらには錠剤の硬度が低くなるなど、問題点が多く、好適な製剤を得ることが困難であった。この乳糖による溶出遅延は結晶セルロースを添加することによって改善できるものの、錠剤の硬度は改善されず、しかも結晶セルロースはＫＭＤ−３２１３と相互作用を起こして分解物が生じやすいなどの問題点があり、本発明の経口固形医薬においては不適である。本発明者はさらに検討を進め、賦形剤については、Ｄ−マンニトールが相互作用も少なく、製造上の問題もなく、極めて良好な溶出特性を確保でき、最も好適であることを見出した。 First, as a result of examining the excipients, the most commonly used lactose has a number of problems such as a tendency to lower the dissolution characteristics, although it does not cause a change in the formulation, and the hardness of the tablet is low. It was difficult to obtain a formulation. Although the dissolution delay due to lactose can be improved by adding crystalline cellulose, the hardness of the tablet is not improved, and there is a problem that the crystalline cellulose easily interacts with KMD-3213 to easily generate a decomposition product. It is not suitable for the oral solid medicine of the present invention. The present inventor further investigated and found that D-mannitol is most suitable as an excipient because it has little interaction, no problem in production, can ensure extremely good dissolution characteristics.
また、崩壊剤では、カルボキシメチルセルロースカルシウムおよびカルボキシメチルセルロースは配合変化が大きく不適であり、デンプン、低置換度ヒドロキシプロピルセルロース、部分α化デンプンなどが好適である。デンプンとしては、例えばコーンスターチなど、部分α化デンプンとしては、例えば「スターチ１５００（登録商標）」（日本カラコン株式会社製）、「ＰＣＳ（登録商標）」（旭化成株式会社製）などを挙げることができる。 As disintegrants, carboxymethylcellulose calcium and carboxymethylcellulose are unsuitable because of great change in formulation, and starch, low-substituted hydroxypropylcellulose, partially pregelatinized starch and the like are suitable. Examples of the starch include corn starch, and examples of the partially pregelatinized starch include “Starch 1500 (registered trademark)” (manufactured by Nippon Colorcon Co., Ltd.) and “PCS (registered trademark)” (manufactured by Asahi Kasei Corporation). it can.
結合剤では、ヒドロキシプロピルメチルセルロースおよびヒドロキシプロピルセルロースはいずれもある程度配合変化を起こし、好適ではない。 As binders, both hydroxypropyl methylcellulose and hydroxypropylcellulose undergo some change in formulation and are not suitable.
滑沢剤では、ステアリン酸マグネシウム、ステアリン酸カルシウムおよびタルクはいずれも特に配合変化を起こさず、使用可能である。 As the lubricant, any of magnesium stearate, calcium stearate and talc can be used without causing any particular change in the composition.
界面活性剤では、マクロゴール（ポリエチレングリコール）、ポリオキシエチレン［１０５］ポリオキシプロピレン［５］グリコールおよびクエン酸トリエチルなどは配合変化が大きく不適である。 Among surfactants, macrogol (polyethylene glycol), polyoxyethylene [105] polyoxypropylene [5] glycol, triethyl citrate and the like are not suitable because of great change in formulation.
以上のような知見に基づいて良好と考えられる添加剤を選定し、通常の方法により製剤を製造すべく検討を行った。まず、操作が簡便で工程も少ない乾式法で製造したところ、粉砕、混合または造粒工程において、粉砕物、混合物または造粒物が静電気を帯びて流動性が低下し、特にカプセル剤の充填工程における操作性が極めて悪く、しかも充填量のバラツキが大きくなり、充填精度が低くなることが判明した。 Based on the above findings, an additive considered to be good was selected, and studies were conducted to produce a preparation by an ordinary method. First, it was manufactured by a dry method with simple operation and few processes. In the pulverization, mixing or granulation process, the pulverized product, mixture or granulated product was charged with static electricity, and the fluidity was lowered. It has been found that the operability in is extremely poor, the variation in the filling amount increases, and the filling accuracy decreases.
このような、カプセル剤の充填工程または錠剤の打錠工程における操作性や充填精度を向上させるために滑沢剤が使用される。ＫＭＤ−３２１３は元々付着性が強く、さらに、乾式法の場合、上記のように静電気の帯電も加わり、混合物または造粒物の流動性がさらに低下するため、滑沢剤がより多く必要となるが、この滑沢剤は一般に撥水性のため溶出時間の遅延を引き起こす。 In order to improve the operability and filling accuracy in the capsule filling step or tablet pressing step, a lubricant is used. KMD-3213 originally has strong adhesion, and in the case of the dry method, static charge is also added as described above, and the fluidity of the mixture or granulated product is further reduced, so that more lubricant is required. However, this lubricant generally causes a delay in elution time due to water repellency.
本発明者らは、上記のような知見の下に、添加剤の種類、組み合わせ、使用比率、製造方法等につき鋭意検討を加え、製造工程における操作性もよく、含有量の精度も高く、溶出特性に優れ、ＫＭＤ−３２１３の作用を効果的に発揮させうる、極めて実用性の高い製剤を得ることができた。 Based on the knowledge as described above, the present inventors have intensively studied the types, combinations, usage ratios, production methods, etc. of additives, and have good operability in the production process, high content accuracy, and elution. It was possible to obtain a highly practical preparation having excellent characteristics and capable of effectively exhibiting the action of KMD-3213.
先ず、滑沢剤による溶出時間の遅延は、滑沢剤の使用量を抑え、混合時間を短縮することによってある程度改善できること、具体的には、滑沢剤の使用量を約１％以下、好ましくは約０．６〜約０．８％に抑え、短時間で、好ましくは約３分〜約５分で混合することによって良好な溶出特性を保持することができることを見出した。そこで、乾式法を湿式法に換えて造粒し、滑沢剤の使用量を約１％以下とし、混合時間を約３分とすることによって、混合物の流動性も良好で、操作性もよく、充填精度の高い製剤を製造することができた。 First, the elution time delay due to the lubricant can be improved to some extent by suppressing the amount of lubricant used and shortening the mixing time. Specifically, the amount of lubricant used is preferably about 1% or less, preferably Has been found to be able to maintain good elution characteristics by mixing to about 0.6 to about 0.8% and mixing in a short time, preferably from about 3 minutes to about 5 minutes. Therefore, granulation is performed by changing the dry method to the wet method, the amount of lubricant used is about 1% or less, and the mixing time is about 3 minutes, so that the fluidity of the mixture is good and the operability is also good. It was possible to produce a preparation with high filling accuracy.
しかしながら、本発明の医薬に活性成分として含有されるＫＭＤ−３２１３は付着性が強いため、特にカプセル剤については、滑沢剤を約１％以下に抑えた場合、スティッキングなどの充填障害を起こす可能性が高く、滑沢剤を約１％以下に抑えることには危険性が伴う。このことから、滑沢剤を約１％以上添加した場合でも溶出時間遅延を改善できる方法を見出すべくさらに検討した結果、固形の親水性または界面活性作用を示す添加剤を加えることにより溶出時間の遅延が顕著に抑えられ、良好な溶出特性を持つ製剤を製造できることを見出した。 However, since KMD-3213 contained as an active ingredient in the medicament of the present invention has strong adhesion, particularly in capsules, if the lubricant is suppressed to about 1% or less, filling troubles such as sticking may occur. It is dangerous, and there is a risk in keeping the lubricant below about 1%. From this, as a result of further investigation to find a method that can improve the elution time delay even when a lubricant is added in an amount of about 1% or more, the addition of an additive exhibiting a solid hydrophilicity or a surface active action reduces the elution time. It has been found that the preparation can be produced with significantly reduced delay and good dissolution characteristics.
この添加剤の溶出時間遅延改善効果は滑沢剤との組み合わせによって異なり、例えば滑沢剤としてステアリン酸マグネシウムを使用した場合、ラウリル硫酸ナトリウムが最も好ましく、ショ糖脂肪酸エステル類、軽質無水ケイ酸、ポリオキシエチレン［１０５］ポリオキシプロピレン［５］グリコールなどでは効果が弱い。ラウリル硫酸ナトリウムは、ステアリン酸マグネシウム１部に対して約２〜約０．１部、好ましくは約０．５部の添加で十分な改善効果を発揮し、良好な溶出特性を維持することができる。 The elution time delay improving effect of this additive varies depending on the combination with the lubricant, for example, when magnesium stearate is used as the lubricant, sodium lauryl sulfate is most preferable, sucrose fatty acid esters, light anhydrous silicic acid, Polyoxyethylene [105] polyoxypropylene [5] glycol or the like has a weak effect. Sodium lauryl sulfate exhibits a sufficient improvement effect by adding about 2 to about 0.1 part, preferably about 0.5 part, with respect to 1 part of magnesium stearate, and can maintain good elution characteristics. .
また、ラウリル硫酸ナトリウム添加による溶出時間遅延改善効果は添加方法によって大きく異なり、顆粒製造工程においてラウリル硫酸ナトリウムを水に溶解し、結合水と合わせて添加（以下、顆粒内添加という）すると、溶出試験開始直後（５分値）の溶出率が低くなる傾向がある。この立ち上がりの遅延を解消すべく検討した結果、ラウリル硫酸ナトリウムを、顆粒製造後滑沢剤と合わせて添加（以下、後末添加という）することにより解消できる事を見出した。 In addition, the dissolution time delay improvement effect due to the addition of sodium lauryl sulfate varies greatly depending on the method of addition. In the granule production process, sodium lauryl sulfate is dissolved in water and added together with bound water (hereinafter referred to as intragranular addition). The elution rate immediately after the start (5 minute value) tends to be low. As a result of studies to eliminate the delay in the rise, it was found that sodium lauryl sulfate can be eliminated by adding it together with a lubricant after granule production (hereinafter referred to as “late addition”).
本発明の経口固形医薬に活性成分として含有されるＫＭＤ−３２１３は光に対して比較的不安定で、保存方法によっては経時的に活性成分の含有量が減少するため、保存及び取扱いに注意を要する。従って、通常の製剤の場合、遮光性の包装での保存が必須であるが、不透明の包装では異物等の混入の判別が困難で、不良品の検査に支障をきたす危険性が高く、さらに、実際に服用する患者は、遮光包装から取り出した状態で保管することも予想されるため、遮光包装の必要のない光安定性の高い製剤が望まれる。 KMD-3213 contained as an active ingredient in the oral solid medicine of the present invention is relatively unstable to light, and depending on the storage method, the content of the active ingredient decreases with time. Cost. Therefore, in the case of normal preparations, it is essential to preserve in light-shielding packaging, but in opaque packaging, it is difficult to determine the contamination of foreign substances, and there is a high risk of hindering the inspection of defective products. The patient who actually takes the medicine is expected to be stored in a state where it is taken out from the light-shielding package. Therefore, a highly light-stable preparation which does not require the light-shielding package is desired.
このため、カプセルまたはコーティング剤に配合させるに好適な遮光性物質について検討した結果、遮光性物質としては酸化チタンが最も好適であり、酸化チタンを配合したカプセルまたは酸化チタンを配合したコーティング剤を使用することによって、極めて良好な、光安定性の高いカプセル剤または錠剤を製造できることを見出した。 For this reason, as a result of investigating a light-shielding substance suitable for incorporation into capsules or coating agents, titanium oxide is most suitable as the light-shielding substance, and capsules containing titanium oxide or coating agents containing titanium oxide are used. By doing so, it was found that a capsule or tablet having extremely good photostability can be produced.
光安定性は、各光分解物（類縁物質、以下類縁物質という）の量（％）および全類縁物質の総量（％）について各々上限規格を設定し、基準曝光量における類縁物質の生成量が設定規格以下であるかなどによって判定される。病院薬局の照明の基準は、ＪＩＳ規格に、３００〜７５０ルクス／時間とされている。照射時間は１日平均約８時間程度と考えられ、医薬品の保存期間は最大６ヶ月と考えられる事から、基準曝光量としては、光量を最大値の７５０ルクス／時間とし、１日の照射時間を約８時間とした時の、１８０日間の曝光に相当する約１０８万ルクス／時間の曝光量に、測定誤差を考慮した約１２０万ルクス／時間程度とされている。一方、医療用医薬品のガイドラインには、光安定性試験の曝光量として、総照度１２０万ルクス／時間以上とされている。従って、医療用医薬品の場合、この約１２０万ルクス／時間の曝光量での安定性試験において安定であることが求められる。 For light stability, upper limit standards are set for the amount (%) of each photodegradable product (related substances, hereinafter referred to as related substances) and the total amount of all related substances (%). Judgment is made based on whether it is below the set standard. The standard for lighting in hospital pharmacies is 300 to 750 lux / hour according to JIS standards. Irradiation time is considered to be about 8 hours on average per day, and the storage period of pharmaceuticals is considered to be a maximum of 6 months. Therefore, the standard exposure is 750 lux / hour, which is the maximum value, When the exposure time is about 8 hours, the exposure amount is about 1.08 million lux / hour corresponding to 180 days of exposure, and about 1.2 million lux / hour in consideration of measurement error. On the other hand, according to the guidelines for ethical drugs, the total illumination intensity is 1.2 million lux / hour or more as the exposure dose in the photostability test. Therefore, in the case of an ethical drug, it is required to be stable in the stability test at an exposure dose of about 1.2 million lux / hour.
本発明の経口固形医薬に活性成分として含有されるＫＭＤ−３２１３については約６種の類縁物質が確認されているが、暫定的に規格を、その中の最大の類縁物質ａが４％以下、それ以外の類縁物質ｂ〜ｆが各々１％以下で、その他の微量の類縁物質を含めた全類縁物質の総量が５％以下と設定し、約１２０万ルクス／時間の曝光量で適合できる遮光性を有するカプセルまたはコーティング剤を製造すべく検討を行った。 About 6 kinds of related substances have been confirmed for KMD-3213 contained as an active ingredient in the oral solid medicine of the present invention. However, provisionally, the maximum related substance a is 4% or less, Other related substances b to f are 1% or less each, and the total amount of all related substances including other minute related substances is set to 5% or less. A study was conducted to produce a capsule or a coating agent having properties.
その結果、遮光性物質として酸化チタンが最も好適であり、酸化チタンを配合したカプセルまたはコーティング剤を使用することにより光安定性の高い固形医薬を製造できることを見出した。 As a result, it has been found that titanium oxide is most suitable as a light-shielding substance, and that a solid medicine having high photostability can be produced by using a capsule or coating agent containing titanium oxide.
酸化チタンの配合量は多い程遮光性は高くなるが、特にカプセルの場合、配合量が多くなるとカプセルの強度が低下する。好適な配合量は、製剤の大きさなどにより適宜決定される。例えばカプセルの場合、約３％以上、好適には約３．４〜３．６％配合する事により好適な遮光性を発揮することができる。錠剤の場合は、錠剤の表面積、コーティング剤の量などにより決定されるが、概ね、錠剤の表面積に対して０．５ｍｇ／平方ｃｍ以上，好適には１．１ｍｇ／平方ｃｍ以上コーティングすることにより好適な遮光性を発揮することができる。 The greater the blending amount of titanium oxide, the higher the light shielding property. However, in the case of capsules in particular, the greater the blending amount, the lower the capsule strength. A suitable amount is appropriately determined depending on the size of the preparation. For example, in the case of a capsule, a suitable light-shielding property can be exhibited by blending about 3% or more, preferably about 3.4 to 3.6%. In the case of a tablet, it is determined by the surface area of the tablet, the amount of the coating agent, etc., but is generally 0.5 mg / square cm or more, preferably 1.1 mg / square cm or more with respect to the tablet surface area. A suitable light-shielding property can be exhibited.
これまで、ＫＭＤ−３２１３、若しくはその薬理学的に許容される塩、またはそれらの薬理学的に許容される溶媒和物を活性成分として含有する医薬品組成物については、例えば、特許文献１または特許文献２のように、極めて一般的な記載がなされているにすぎず、具体的には全く報告されていない。
So far, for pharmaceutical compositions containing KMD-3213, or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable solvate thereof as an active ingredient, for example,
しかしながら、上記のとおり、活性成分としてＫＭＤ−３２１３、若しくはその薬理学的に許容される塩、またはそれらの薬理学的に許容される溶媒和物を含有する経口固形医薬は、一般的な製造方法で調製した場合、問題点が多く、実用に供されうるものではない。特許文献１または特許文献２にはこれらの問題点についても、それを解決する方法についても全く報告も示唆もされていない。
However, as described above, an oral solid medicine containing KMD-3213, or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable solvate thereof as an active ingredient is a general production method. When prepared with, there are many problems and it cannot be put to practical use.
本発明の経口固形医薬において活性成分として含有されるＫＭＤ−３２１３は公知の化合物であり、文献記載の方法、たとえば特許文献１記載の方法により製造することができる。
KMD-3213 contained as an active ingredient in the oral solid medicine of the present invention is a known compound, and can be produced by a method described in the literature, for example, a method described in
本発明の経口固形医薬において活性成分として含有されるＫＭＤ−３２１３の薬理学的に許容される塩としては、例えば、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸などの鉱酸との酸付加塩、酢酸、プロピオン酸、酪酸、蓚酸、クエン酸、コハク酸、酒石酸、フマル酸、マロン酸、マレイン酸、リンゴ酸、乳酸、アジピン酸、安息香酸、サリチル酸、メタンスルホン酸、ベンゼンスルホン酸、ｐ−トルエンスルホン酸、グルタミン酸、アスパラギン酸などの有機酸との酸付加塩を挙げることができる。また、溶媒和物としては、水またはエチルアルコールなどとの溶媒和物を挙げることができる。 Examples of the pharmacologically acceptable salt of KMD-3213 contained as an active ingredient in the oral solid medicine of the present invention include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Acid addition salts with mineral acids, acetic acid, propionic acid, butyric acid, succinic acid, citric acid, succinic acid, tartaric acid, fumaric acid, malonic acid, maleic acid, malic acid, lactic acid, adipic acid, benzoic acid, salicylic acid, methanesulfonic acid And acid addition salts with organic acids such as benzenesulfonic acid, p-toluenesulfonic acid, glutamic acid and aspartic acid. Examples of solvates include solvates with water or ethyl alcohol.
本発明の経口固形医薬、例えば、カプセル剤は以下のようにして製造することができる。すなわち、ＫＭＤ−３２１３、若しくはその薬理学的に許容される塩、またはそれらの薬理学的に許容される溶媒和物に、賦形剤、好ましくはＤ−マンニトールを加え、さらに必要に応じて適当な結合剤および崩壊剤を加え、適当な濃度の結合剤の水溶液を加えて練合し、必要に応じ篩過して顆粒を製し、これに滑沢剤、好ましくは０．５〜２．０％のステアリン酸マグネシウム、および固形の親水性または界面活性作用を示す添加剤、好ましくはラウリル硫酸ナトリウムを、使用比率１０：１〜１０：２０、さらに好ましくは１０：５〜１０：１０、なおさらに好ましくは１０：５の割合で加えて混合し、適当なカプセル、好ましくは酸化チタンを約３％以上、さらに好ましくは約３．４〜３．６％配合したカプセルに充填して製造する。 The oral solid medicine of the present invention, for example, a capsule, can be produced as follows. That is, an excipient, preferably D-mannitol is added to KMD-3213, or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable solvate thereof, and further, if necessary, A binder and a disintegrant are added, and an aqueous solution of a binder having an appropriate concentration is added and kneaded. If necessary, the mixture is sieved to produce granules, and a lubricant, preferably 0.5-2. 0% magnesium stearate and solid hydrophilic or surfactant additive, preferably sodium lauryl sulfate, in a use ratio of 10: 1 to 10:20, more preferably 10: 5 to 10:10, and more Preferably, the mixture is added at a ratio of 10: 5 and mixed, and filled into a suitable capsule, preferably a capsule containing about 3% or more of titanium oxide, more preferably about 3.4 to 3.6%.
また、錠剤は以下のようにして製造することができる。すなわち、カプセル剤と同様にして顆粒を製し、これに滑沢剤、好ましくはステアリン酸マグネシウムを、使用量１％以下、好ましくは約０．６〜約０．８％、さらに好ましくは約０．７％加えて混合し、一般的な方法により打錠して素錠を製造する。さらに、適当な溶媒に、フィルムコーティング剤、遮光剤、好ましくは酸化チタン、および可塑剤を加え、また必要に応じて適当な滑沢剤、凝集防止剤、着色剤を加えて溶解または分散させてコーティング溶液を製し、これを素錠に噴霧コーティングして製造する。酸化チタンの量は、錠剤の表面積に対して０．５ｍｇ／平方ｃｍ以上，好適には１．１ｍｇ／平方ｃｍ以上であれば十分である。 Moreover, a tablet can be manufactured as follows. That is, a granule is produced in the same manner as a capsule, and a lubricant, preferably magnesium stearate, is used in an amount of 1% or less, preferably about 0.6 to about 0.8%, more preferably about 0. 7% is added and mixed, and tableted by a general method to produce an uncoated tablet. Furthermore, a film coating agent, a light-shielding agent, preferably titanium oxide, and a plasticizer are added to an appropriate solvent, and if necessary, an appropriate lubricant, an anti-aggregation agent, and a colorant are added and dissolved or dispersed. A coating solution is prepared and spray coated on the uncoated tablets. The amount of titanium oxide is sufficient to be 0.5 mg / square cm or more, preferably 1.1 mg / square cm or more with respect to the surface area of the tablet.
ＫＭＤ−３２１３は、α１−ＡＲ遮断作用を有し、しかも血圧に対する影響が少なく、前立腺肥大症等に起因する排尿障害の治療剤として極めて有用な化合物である。また、α１−ＡＲ遮断作用を有する塩酸プラゾシンや塩酸タムスロシンが膀胱頸部硬化症、慢性前立腺炎、神経因性膀胱などの排尿障害に有効であることも報告されている。 KMD-3213 has an α 1 -AR blocking action and has little effect on blood pressure, and is an extremely useful compound as a therapeutic agent for dysuria caused by prostatic hypertrophy. It has also been reported that prazosin hydrochloride and tamsulosin hydrochloride having an α 1 -AR blocking action are effective for urination disorders such as bladder neck sclerosis, chronic prostatitis, and neurogenic bladder.
従って、ＫＭＤ−３２１３は、前立腺肥大症、尿道狭窄、尿道結石や腫瘍など（以下、前立腺肥大症等という）の尿道の器質的閉塞に伴う排尿障害はいうまでもなく、排尿支配神経の異常に伴う排尿障害およびその何れにも該当しない、膀胱頸部硬化症、慢性前立腺炎、不安定膀胱などの尿道の機能的閉塞に伴う排尿障害の治療剤として期待できる。 Accordingly, KMD-3213 is not limited to dysuria due to organic obstruction of the urethra such as benign prostatic hypertrophy, urethral stricture, urethral stone or tumor (hereinafter referred to as prostatic hypertrophy, etc.), but it also causes abnormalities in the urinary control nerve. It can be expected as a therapeutic agent for dysuria associated with functional obstruction of the urethra such as bladder cervical sclerosis, chronic prostatitis, unstable bladder, etc., which does not fall under any of the accompanying dysuria.
排尿支配神経の異常に伴う排尿障害とは、脳血管障害や脳腫瘍などの脳障害、脊髄損傷などの脊髄障害、糖尿病、腰部脊柱管狭窄症などの末梢神経障害などによる尿道または膀胱の支配神経の不調によって生じる排尿障害であり、男女共通に生じ、神経因性膀胱と総称される。 The dysuria associated with abnormalities in the urinary control nerves includes brain disorders such as cerebrovascular disorders and brain tumors, spinal cord disorders such as spinal cord injury, peripheral nerve disorders such as diabetes and lumbar spinal canal stenosis, etc. It is a dysuria caused by a disorder, occurs in both men and women, and is collectively referred to as neurogenic bladder.
また、尿道の器質的障害及び排尿支配神経の異常がなく、尿道の機能的閉塞に伴う排尿障害とは、上記の膀胱頸部硬化症、慢性前立腺炎、不安定膀胱のほか、排尿困難症、膀胱頸部閉塞症、尿道症候群、排尿筋−括約筋協調不全、慢性膀胱炎、前立腺痛、ヒンマン（Ｈｉｎｍａｎ）症候群、ファウラー症候群、心因性排尿障害、薬剤性排尿障害、加齢による排尿障害などであり、下部尿路症と総称される。 In addition, there is no abnormality of the urethral organic disorder and dysuria, and dysuria due to functional blockage of the urethra includes bladder cervical sclerosis, chronic prostatitis, unstable bladder, dysuria, Bladder neck obstruction, urethral syndrome, detrusor-sphincter dysfunction, chronic cystitis, prostate pain, Hinman syndrome, Fowler syndrome, psychogenic dysuria, drug-induced dysuria, dysuria due to aging, etc. Yes, collectively referred to as lower urinary tract disease.
本発明の医薬は前記したように、活性成分の含有量の精度が高く、しかも溶出特性に優れており、ＫＭＤ−３２１３の作用を効果的に発揮させることができる。従って、本発明の医薬は、尿道の器質的閉塞に伴う排尿障害の前立腺肥大症等、排尿支配神経の異常に伴う排尿障害の神経因性膀胱または尿道の機能的閉塞に伴う排尿障害の下部尿路症の治療剤として極めて有用である。 As described above, the medicament of the present invention has high accuracy of the content of the active ingredient and excellent elution characteristics, and can effectively exert the action of KMD-3213. Therefore, the medicament of the present invention is a lower urine of dysuria associated with functional obstruction of neurogenic bladder or urethra of urination disorder associated with abnormality of urinary control nerve such as prostatic hypertrophy of dysuria associated with organic obstruction of urethra. It is extremely useful as a therapeutic agent for uropathy.
本発明の上記医薬を実際の治療に使用する場合、活性成分の投与量は、患者の性別、年齢、体重、疾患の程度等によって適宜決定されるが、概ね成人１日あたり、１〜５０ｍｇ、好ましくは４〜２０ｍｇの範囲で投与する。 When the above medicament of the present invention is used for actual treatment, the dose of the active ingredient is appropriately determined depending on the sex, age, weight, degree of disease, etc. of the patient, and is generally 1 to 50 mg per adult day, Preferably it is administered in the range of 4-20 mg.
本発明の医薬には、活性成分として、ＫＭＤ−３２１３、若しくはその薬理学的に許容される塩、またはそれらの薬理学的に許容される溶媒和物の他に、さらにＫＭＤ−３２１３以外のα１−ＡＲ遮断薬、抗コリン薬、抗炎症薬および抗菌薬の群から選ばれる少なくとも１種を含有させてもよい。 In the medicament of the present invention, as an active ingredient, in addition to KMD-3213, or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable solvate thereof, α other than KMD-3213 You may contain at least 1 sort (s) chosen from the group of 1- AR blocker, an anticholinergic agent, an anti-inflammatory agent, and an antibacterial agent.
本発明の医薬はさらに、ＫＭＤ−３２１３以外のα１−ＡＲ遮断薬、抗コリン薬、抗炎症薬および抗菌薬の群から選ばれる少なくとも１種を活性成分として含有する医薬と組み合わせて使用してもよい。 The medicament of the present invention is further used in combination with a medicament containing as an active ingredient at least one selected from the group of α 1 -AR blockers other than KMD-3213, anticholinergic agents, anti-inflammatory agents and antibacterial agents. Also good.
このような場合、活性成分として含有させるＫＭＤ−３２１３、若しくはその薬理学的に許容される塩、またはそれらの薬理学的に許容される溶媒和物およびＫＭＤ−３２１３以外のα１−ＡＲ遮断薬、抗コリン薬、抗炎症薬および抗菌薬の使用量を適宜低減してもよい。 In such a case, KMD-3213 contained as an active ingredient, or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable solvate thereof and an α 1 -AR blocking agent other than KMD-3213 The amount of anticholinergic agent, anti-inflammatory agent and antibacterial agent used may be appropriately reduced.
本発明の内容を以下の試験例および実施例によりさらに詳細に説明する。 The contents of the present invention will be described in more detail with reference to the following test examples and examples.
試験例１
配合変化確認試験
ＫＭＤ−３２１３および経口固形製剤の製造に用いられる各種医薬品添加物について、使用量の多い賦形剤、崩壊剤および結合剤は１：１、使用量の少ないその他の添加剤は１０：１の比率で混合し、下記(1)及び(2)の保存条件で保存した後、配合変化を確認した。なお、分解物は下記ＨＰＬＣ分析方法により定量し、変色は肉眼観察で行った。
Test example 1
Formulation change confirmation test For various pharmaceutical additives used in the manufacture of KMD-3213 and oral solid preparations, the excipients, disintegrants and binders used in large amounts were 1: 1, and other additives used in small amounts were 10 The mixture was mixed at a ratio of 1: 1 and stored under the following storage conditions (1) and (2), and then the blending change was confirmed. The decomposed product was quantified by the following HPLC analysis method, and the discoloration was performed by visual observation.
保存条件
(1)温度６０℃、相対湿度８０％、３週間
(2)温度４０℃、相対湿度７５％、４ヶ月間
Storage conditions
(1)
(2)
ＨＰＬＣ分析方法
ＫＭＤ−３２１３ ５ｍｇに相当する混合末を採り、メタノール１０ｍLに溶かし、振とう器を用いて１０分間振とうした。この液４ｍLを採り、メタノールを加えて５ｍLとした液を、孔径０．４５μｍのメンブランフィルターでろ過し、ろ液を試料溶液とした。
試料溶液５μLにつき、次の条件でＨＰＬＣ測定を行ない、溶媒ピークを除いた総ピーク面積に対する各類縁物質ピーク面積の百分率を求めた。
ＨＰＬＣ測定条件
測定波長：２２５ｎｍ
カラム：Ｃａｐｃｅｌｌ Ｐａｃｋ Ｃ１８ ＵＧ１２０（株式会社資生堂）
カラム温度：約２５℃
移動相：リン酸２水素カリウム６．８ｇとリン酸１水素２ナトリウム・１２水塩１７．９ｇに水を加えて全量を１０００ｍＬとした液と、アセトニトリルとの７：３の混合溶液。
液量：１．０ｍＬ／分
測定時間：４０分
HPLC analysis method KMD-3213 A mixed powder corresponding to 5 mg was taken, dissolved in 10 mL of methanol, and shaken for 10 minutes using a shaker. 4 mL of this solution was taken, and a solution made up to 5 mL by adding methanol was filtered through a membrane filter having a pore size of 0.45 μm, and the filtrate was used as a sample solution.
For 5 μL of the sample solution, HPLC measurement was performed under the following conditions, and the percentage of each related substance peak area with respect to the total peak area excluding the solvent peak was determined.
HPLC measurement conditions Measurement wavelength: 225 nm
Column: Capcell Pack C18 UG120 (Shiseido Co., Ltd.)
Column temperature: about 25 ° C
Mobile phase: A 7: 3 mixed solution of a solution in which 6.8 g of potassium dihydrogen phosphate and 17.9 g of disodium hydrogen hydrogen phosphate · 12 hydrate were added with water to a total volume of 1000 mL and acetonitrile.
Liquid volume: 1.0 mL / min Measurement time: 40 minutes
結果は、(1)の保存条件での結果が表１に示すとおりであり、(2)の保存条件での結果が表２に示すとおりである。 As for the results, the results under the storage conditions (1) are as shown in Table 1, and the results under the storage conditions (2) are as shown in Table 2.
表１および表２に示すとおり、賦形剤ではＤ−マンニトールが最も好ましく、結晶セルロースは配合変化を起こし不適であった。崩壊剤ではデンプン（コーンスターチ）が最も好ましく、カルボキシメチルセルロースカルシウムおよびカルボキシメチルセルロースは配合変化が大きく不適であった。結合剤のヒドロキシプロピルメチルセルロースおよびヒドロキシプロピルセルロースはいずれもある程度配合変化を起こし、あまり良好な結果でなかった。界面活性剤のマクロゴール、ポリオキシエチレン［１０５］ポリオキシプロピレン［５］グリコールおよびクエン酸トリエチルなどは配合変化が大きく不適であった。 As shown in Tables 1 and 2, D-mannitol was most preferable as the excipient, and crystalline cellulose was unsuitable due to a change in the composition. As the disintegrant, starch (corn starch) was most preferable, and carboxymethylcellulose calcium and carboxymethylcellulose were not suitable because of great change in formulation. The binders hydroxypropylmethylcellulose and hydroxypropylcellulose both had some blending changes and were not very good. Surfactant macrogol, polyoxyethylene [105] polyoxypropylene [5] glycol, triethyl citrate and the like were not suitable because of great change in formulation.
試験例２
ステアリン酸マグネシウムの混合時間と溶出時間遅延作用確認試験
賦形剤としてＤ−マンニトールを、崩壊剤として部分α化デンプン「スターチ１５００（登録商標）」（日本カラコン株式会社製）をそれぞれ選択し、滑沢剤のステアリン酸マグネシウムを約１％添加したときの、混合時間と溶出時間遅延との相関について確認した。
Test example 2
Confirmation test for delayed action of mixing magnesium stearate and elution time Select D-mannitol as excipient and partially pregelatinized starch "Starch 1500 (registered trademark)" (manufactured by Nippon Colorcon Co., Ltd.) The correlation between mixing time and elution time delay was confirmed when about 1% of the magnesium stearate was added.
表３に示す処方によりカプセル剤を製造し、以下の溶出試験方法により、溶出時間を測定した。 Capsules were produced according to the formulation shown in Table 3, and the dissolution time was measured by the following dissolution test method.
溶出試験方法
被験製剤１個をシンカーに入れて容器の中央底部に沈め、試験液に精製水５００ｍＬを用い、日本薬局方溶出試験法第２法（パドル法）により、回転数５０回／分で試験を行い、試験開始後５分、１０分、１５分、２０分および３０分後に溶出液５ｍＬを採取し、直ちに同容量の試験液を補充した。採取した溶出液を０．４５μｍのメンブランフィルターでろ過し、最初のろ液４ｍＬを除いた残りのろ液１ｍＬを試料溶液とした。
別に、ＫＭＤ−３２１３標準品約０．０１ｇを精密に量り、精製水に溶解し、正確に１００ｍＬとした。この液８ｍＬを正確に量り、精製水を加えて正確に１００ｍＬとし、標準液とした。
試料溶液および標準液１００μＬにつき下記条件で液体クロマトグラフ測定を行い、試料溶液および標準液のＫＭＤ−３２１３のピーク面積から溶出率を算出した。なお、溶出率は、各製剤について無作為に６個抽出して試験を行い、その平均を取った。
Dissolution test method Put one test preparation in a sinker, sink it in the center bottom of the container, use 500 mL of purified water as the test solution, and use the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method) at a rotation speed of 50 times / minute. The test was performed, and 5 mL, 5 minutes, 15 minutes, 20 minutes and 30 minutes after the start of the test, 5 mL of the eluate was collected and immediately replenished with the same volume of the test solution. The collected eluate was filtered through a 0.45 μm membrane filter, and 1 mL of the remaining filtrate excluding the first 4 mL of filtrate was used as a sample solution.
Separately, about 0.01 g of KMD-3213 standard product was accurately weighed and dissolved in purified water to make exactly 100 mL. 8 mL of this solution was accurately weighed and purified water was added to make exactly 100 mL, which was used as a standard solution.
Liquid chromatographic measurement was performed on 100 μL of the sample solution and standard solution under the following conditions, and the elution rate was calculated from the peak areas of KMD-3213 of the sample solution and standard solution. For the dissolution rate, 6 samples were randomly extracted for each preparation and tested, and the average was taken.
ＨＰＬＣ測定条件
測定波長：２７０ｎｍ
カラム：Ｉｎｅｒｔｓｉｌ ＯＤＳ−３（ジーエルサイエンス株式会社）
カラム温度：約２５℃
移動相：リン酸２水素ナトリウム２水塩３．９ｇおよび希リン酸水溶液（１→２０）２．５ｍＬに水を加えて全量１０００ｍＬとした液と、アセトニトリルとの５：２混合溶液
液量：１．０ｍＬ／分
HPLC measurement conditions Measurement wavelength: 270 nm
Column: Inertsil ODS-3 (GL Sciences Inc.)
Column temperature: about 25 ° C
Mobile phase: a 5: 2 mixed solution of a solution obtained by adding water to 3.9 g of sodium dihydrogen phosphate dihydrate and 2.5 mL of dilute phosphoric acid aqueous solution (1 → 20) to make a total volume of 1000 mL, and acetonitrile 1.0 mL / min
なお、ステアリン酸マグネシウムを添加した処方（処方Ｂ）については、混合時間１分（処方Ｂ・１分）、３分（処方Ｂ・３分）および７分（処方Ｂ・７分）の時点でそれぞれ混合物を取り出し、カプセルに充填した。また、カプセル充填は手充填により行った。
試験結果は図１に示すとおりである。図１に示すとおり、処方Ｂ・１分でも多少の溶出時間の遅延が認められ、処方Ｂ・３分ではかなりの溶出時間の遅延が認められた。
In addition, about the prescription (prescription B) to which magnesium stearate was added, the mixing time was 1 minute (prescription B · 1 minute), 3 minutes (prescription B · 3 minutes) and 7 minutes (prescription B · 7 minutes). Each mixture was removed and filled into capsules. Capsule filling was performed by hand filling.
The test results are as shown in FIG. As shown in FIG. 1, a slight delay in dissolution time was observed even in Formulation B · 1 minute, and a considerable delay in dissolution time was observed in Formulation B · 3 minutes.
試験例３
ステアリン酸マグネシウムの溶出時間遅延に対する各種添加剤の作用確認試験
各種添加剤について、カプセル剤における、滑沢剤のステアリン酸マグネシウム約１％添加による溶出時間遅延に対する改善作用の確認試験を行った。試験例２における処方Ｂに、ステアリン酸マグネシウムと同量の各種添加物を加えた処方（表４）によりカプセル剤を製造し、試験例２と同様の溶出試験方法により、溶出時間を測定した。
なお、各添加剤は、顆粒製造後、ステアリン酸マグネシウムと合わせて添加する後末添加法によった。また、混合時間は５分とした。
試験結果は図２に示すとおり、ラウリル硫酸ナトリウム（処方Ｃ）のみがステアリン酸マグネシウム添加による溶出時間遅延を殆ど解消し、ステアリン酸マグネシウム無添加（処方Ａ）とほぼ同等の溶出特性を示した。
Test example 3
Test for confirming action of various additives on delay in dissolution time of magnesium stearate For various additives, a test for confirming an improvement effect on delay in dissolution time by adding about 1% of magnesium stearate as a lubricant in a capsule was conducted. Capsules were prepared according to a formulation (Table 4) in which the same amount of various additives as magnesium stearate was added to the formulation B in Test Example 2, and the dissolution time was measured by the same dissolution test method as in Test Example 2.
In addition, each additive was based on the terminal powder addition method added together with magnesium stearate after granule manufacture. The mixing time was 5 minutes.
As shown in FIG. 2, the test results showed that only sodium lauryl sulfate (formulation C) almost eliminated the elution time delay due to the addition of magnesium stearate, and showed almost the same elution characteristics as no magnesium stearate addition (formulation A).
試験例４
ステアリン酸マグネシウムとラウリル硫酸ナトリウム配合比率と溶出特性確認試験
ステアリン酸マグネシウム添加による溶出時間遅延に対し良好な改善効果を示したラウリル硫酸ナトリウムについて、配合比率と溶出特性改善効果の相関を確認した。表５に示す処方によりカプセル剤を製造し、日本薬局方溶出試験法第２法（パドル法）により、水における溶出時間を測定した。以下の溶出試験方法により、溶出時間を測定した。なお、ＨＰＬＣ測定条件は試験例２と同じである。
Test example 4
Mixing ratio of magnesium stearate and sodium lauryl sulfate and elution characteristics confirmation test For sodium lauryl sulfate which showed a good improvement effect on the elution time delay due to the addition of magnesium stearate, the correlation between the mixing ratio and the elution characteristics improvement effect was confirmed. Capsules were produced according to the formulation shown in Table 5, and the dissolution time in water was measured by the Japanese Pharmacopoeia dissolution test method 2 (paddle method). The dissolution time was measured by the following dissolution test method. The HPLC measurement conditions are the same as in Test Example 2.
溶出試験方法
被験製剤１個をシンカーに入れて容器の中央底部に沈め、試験液に精製水９００ｍＬを用い、日本薬局方溶出試験法第２法（パドル法）により、回転数５０回／分で試験を行い、試験開始後５分、１０分、１５分、２０分および３０分後に溶出液５ｍＬを採取し、直ちに同容量の試験液を補充した。採取した溶出液を遠心分離（３０００回／分、５分以上）した後，その上澄みに濃塩酸１０μＬを加え試料溶液とした。
別に、ＫＭＤ−３２１３標準品約０．０１ｇを精密に量り、０．１Ｎ塩酸に溶かし、正確に１００ｍＬとした。この液２ｍＬを正確に量り、０．１Ｎ塩酸を加えて正確に１００ｍＬとし、標準液とした。
なお、各添加剤は、顆粒製造後、ステアリン酸マグネシウムと合わせて添加する後末添加法とし、混合時間は５分とした。
また、溶出率は、各製剤について無作為に６個抽出して試験を行い、その平均を取った。
Dissolution test method Place one test preparation in a sinker, sink it in the center bottom of the container, use 900 mL of purified water as the test solution, and use the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method) at a rotation speed of 50 times / min. The test was performed, and 5 mL, 5 minutes, 15 minutes, 20 minutes and 30 minutes after the start of the test, 5 mL of the eluate was collected and immediately replenished with the same volume of the test solution. The collected eluate was centrifuged (3000 times / min, 5 minutes or more), and 10 μL of concentrated hydrochloric acid was added to the supernatant to prepare a sample solution.
Separately, about 0.01 g of KMD-3213 standard product was accurately weighed and dissolved in 0.1N hydrochloric acid to make exactly 100 mL. 2 mL of this solution was accurately weighed and 0.1N hydrochloric acid was added to make exactly 100 mL, which was used as a standard solution.
Each additive was added after the granule production and added together with magnesium stearate, and the mixing time was 5 minutes.
In addition, the dissolution rate was randomly extracted for each preparation and tested, and the average was taken.
試験結果は図３に示すとおり、ステアリン酸マグネシウムに対しラウリル硫酸ナトリウム約１０％添加（処方Ｉ）で良好な溶出特性改善効果を発揮し、溶出時間遅延を殆ど解消できた。 As shown in FIG. 3, the test results showed that when about 10% of sodium lauryl sulfate was added to the magnesium stearate (formulation I), a good effect of improving the elution characteristics was exhibited, and the elution time delay was almost eliminated.
実施例１
ＫＭＤ−３２１３ ２．０ｍｇ含有カプセル剤
ＫＭＤ−３２１３ ２．０部、Ｄ−マンニトール １３４．４部、部分α化デンプン「ＰＣＳ（登録商標）」（旭化成株式会社製） ２６．０部および部分α化デンプン「スターチ１５００（登録商標）」（日本カラコン株式会社製） ９．０部の混合物をよく混合し、これに適量の水を加えて練合し、造粒した。造粒物を流動層造粒乾燥機により、給気６０℃で排気４０℃まで乾燥し、篩過して顆粒を製した。これにステアリン酸マグネシウム １．８部およびラウリル硫酸ナトリウム １．８部の混合物を添加し、５分間混合し、カプセルに充填して、１カプセル中２．０ｍｇのＫＭＤ−３２１３を含有するカプセル剤を製した。
Example 1
KMD-3213 2.0 mg-containing capsules KMD-3213 2.0 parts, D-mannitol 134.4 parts, partially pregelatinized starch “PCS (registered trademark)” (manufactured by Asahi Kasei Corporation) 26.0 parts and partial pregelatinization Starch “Starch 1500 (registered trademark)” (manufactured by Nippon Colorcon Co., Ltd.) 9.0 parts of the mixture was mixed well, kneaded with an appropriate amount of water, and granulated. The granulated product was dried with a fluidized bed granulator / dryer at a supply air of 60 ° C. to an exhaust temperature of 40 ° C., and sieved to produce granules. To this was added a mixture of 1.8 parts of magnesium stearate and 1.8 parts of sodium lauryl sulfate, mixed for 5 minutes, filled into capsules to give a capsule containing 2.0 mg of KMD-3213 in one capsule. Made.
実施例２
ＫＭＤ−３２１３ ４．０ｍｇ含有カプセル剤
ＫＭＤ−３２１３ ４．０部、Ｄ−マンニトール １３２．４部、部分α化デンプン「ＰＣＳ（登録商標）」（旭化成株式会社製） ２６．０部および部分α化デンプン「スターチ１５００（登録商標）」（日本カラコン株式会社製） ９．０部の混合物をよく混合し、これに適量の水を加えて練合し、造粒した。造粒物を流動層造粒乾燥機により、給気６０℃で排気４０℃まで乾燥し、篩過して顆粒を製した。これにステアリン酸マグネシウム １．８部およびラウリル硫酸ナトリウム １．８部の混合物を添加し、５分間混合し、カプセルに充填して、１カプセル中４．０ｍｇのＫＭＤ−３２１３を含有するカプセル剤を製した。
Example 2
KMD-3213 4.0 mg-containing capsule KMD-3213 4.0 parts, D-mannitol 132.4 parts, partially pregelatinized starch “PCS (registered trademark)” (manufactured by Asahi Kasei Corporation) 26.0 parts and partial pregelatinization Starch “Starch 1500 (registered trademark)” (manufactured by Nippon Colorcon Co., Ltd.) 9.0 parts of the mixture was mixed well, kneaded with an appropriate amount of water, and granulated. The granulated product was dried with a fluidized bed granulator / dryer at a supply air temperature of 60 ° C. to an exhaust gas of 40 ° C., and sieved to produce granules. To this was added a mixture of 1.8 parts magnesium stearate and 1.8 parts sodium lauryl sulfate, mixed for 5 minutes, filled into capsules to give a capsule containing 4.0 mg of KMD-3213 in one capsule. Made.
実施例３
ＫＭＤ−３２１３ ４．０ｍｇ含有錠剤
ＫＭＤ−３２１３ ４．０部、Ｄ−マンニトール １１７．０部、コーンスターチ ７．０部および低置換度ヒドロキシプロピルセルロース（「Ｌ−ＨＰＣ（登録商標）」、信越化学株式会社製） ７．０部の混合物をよく混合し、これに約１２％のヒドロキシプロピルセルロース水溶液（ヒドロキシプロピルセルロース ４．０部、水 約３０部）を加えて練合し、造粒した。造粒物を流動層造粒乾燥機により、給気６０℃で排気４０℃まで乾燥し、乾燥後粉砕、整粒し、篩過して顆粒を製した。これにステアリン酸マグネシウム １．０部を添加し、３分間混合し、打錠して素錠を製し、コーティング剤でコーティングして１錠中４．０ｍｇのＫＭＤ−３２１３を含有する錠剤を製した。
Example 3
Tablet containing 4.0 mg of KMD-3213 4.0 parts of KMD-3213, 117.0 parts of D-mannitol, 7.0 parts of corn starch and low-substituted hydroxypropylcellulose ("L-HPC (registered trademark)", Shin-Etsu Chemical Co., Ltd. 7.0 parts of the mixture was mixed well, and about 12% aqueous hydroxypropylcellulose solution (4.0 parts of hydroxypropylcellulose, about 30 parts of water) was added and kneaded and granulated. The granulated material was dried with a fluidized bed granulator / dryer at an air supply of 60 ° C. to an exhaust gas of 40 ° C., dried, pulverized, sized, and sieved to produce granules. Add 1.0 parts of magnesium stearate, mix for 3 minutes, compress to make plain tablets, and coat with coating agent to make tablets containing 4.0 mg of KMD-3213. did.
試験例５
溶出時間確認試験
実施例１〜３の製剤について、以下の溶出試験方法により、溶出時間を測定した。なお、ＨＰＬＣ測定条件は試験例２と同じである。
Test Example 5
Dissolution time confirmation test For the preparations of Examples 1 to 3, dissolution time was measured by the following dissolution test method. The HPLC measurement conditions are the same as in Test Example 2.
溶出試験方法
被験製剤１個を、錠剤の場合はそのまま、カプセル剤の場合はシンカーに入れて容器の中央底部に沈め、試験液に精製水９００ｍＬを用い、日本薬局方溶出試験法第２法（パドル法）により、回転数５０回／分で試験を行い、試験開始後５分、１０分、１５分、２０分および３０分後に溶出液５ｍＬを採取し、直ちに同容量の試験液を補充した。採取した溶出液を遠心分離（３０００回／分，５分以上）した後，その上澄みに濃塩酸１０μＬを加え試料溶液とした。
別に、ＫＭＤ−３２１３標準品約０．０１ｇを精密に量り、０．１Ｎ塩酸に溶かし、正確に１００ｍＬとした。実施例１の製剤（２ｍｇ製剤）については、この液２ｍＬを正確に量り、実施例２および３の製剤（４mg製剤）については、この液４ｍＬを正確に量り、それぞれ０．１Ｎ塩酸を加えて正確に１００ｍＬとし、標準液とした。
試料溶液および標準液１００μＬにつき下記条件でＨＰＬＣ測定を行い、試料溶液および標準液のＫＭＤ−３２１３のピーク面積から溶出率を算出した。なお、溶出率は、各製剤について無作為に６個抽出して試験を行い、その平均を取った。
Dissolution test method One test preparation is taken as it is in the case of tablets, and in the case of capsules, it is placed in a sinker and submerged in the center bottom of the container, and 900 mL of purified water is used as a test solution. The paddle method was used to perform the test at a rotation speed of 50 times / minute, and 5 mL, 10 minutes, 15 minutes, 20 minutes and 30 minutes after the start of the test, 5 mL of the eluate was collected and immediately replenished with the same volume of the test solution. . The collected eluate was centrifuged (3000 times / min, 5 minutes or more), and 10 μL of concentrated hydrochloric acid was added to the supernatant to prepare a sample solution.
Separately, about 0.01 g of KMD-3213 standard product was accurately weighed and dissolved in 0.1N hydrochloric acid to make exactly 100 mL. For the formulation of Example 1 (2 mg formulation), accurately measure 2 mL of this solution, and for the formulations of Examples 2 and 3 (4 mg formulation), accurately measure 4 mL of this solution and add 0.1N hydrochloric acid respectively. It was exactly 100 mL and used as a standard solution.
HPLC measurement was performed on 100 μL of the sample solution and standard solution under the following conditions, and the elution rate was calculated from the peak areas of KMD-3213 of the sample solution and standard solution. For the dissolution rate, 6 samples were randomly extracted for each preparation and tested, and the average was taken.
ＨＰＬＣ測定条件
測定波長：２７０ｎｍ
カラム：Ｉｎｅｒｔｓｉｌ ＯＤＳ−３（ジーエルサイエンス株式会社）
カラム温度：約２５℃
移動相：リン酸２水素ナトリウム２水塩３．９ｇおよび希リン酸水溶液（１→２０）２．５ｍＬに水を加えて全量１０００ｍＬとし、この液とアセトニトリルとの５：２混合溶液
液量：１．０ｍＬ／分
HPLC measurement conditions Measurement wavelength: 270 nm
Column: Inertsil ODS-3 (GL Sciences Inc.)
Column temperature: about 25 ° C
Mobile phase: Water was added to 3.9 g of sodium dihydrogen phosphate dihydrate and 2.5 mL of dilute phosphoric acid aqueous solution (1 → 20) to make a total volume of 1000 mL, and a 5: 2 mixed solution of this solution and acetonitrile. 1.0 mL / min
結果は図４に示すとおり、実施例１〜３の全ての製剤において、撹拌時間１０分で９０％以上の溶出率を示し、Ｔ８５％は１０分以下であった。 As a result, as shown in FIG. 4, in all the preparations of Examples 1 to 3, the elution rate was 90% or more at a stirring time of 10 minutes, and T85% was 10 minutes or less.
試験例６
酸化チタン配合カプセルの光安定性試験
酸化チタン１．２％配合カプセル（カプセルＡ）、酸化チタン２．４％配合カプセル（カプセルＢ）および酸化チタン３．６％配合カプセル（カプセルＣ）を用い、実施例１記載の方法に従ってそれぞれのカプセルに充填したカプセル剤について光安定性試験を行った。対照として、酸化チタン１．２％配合カプセル（カプセルＡ）のＰＴＰ包装品をアルミ袋に入れて遮光したものを同様に試験した。
各カプセル剤について、試験開始前、約６７．２万ルクス／時間の曝光後および約１２０万ルクス／時間の曝光後、内容物を取り出し、外観観測および光分解物（類縁物質）の定量を行った。なお、光分解物は下記ＨＰＬＣ分析方法により定量し、変色は肉眼観察で行った。
Test Example 6
Light Stability Test of Titanium Oxide Blended Capsule Titanium oxide 1.2% blended capsule (capsule A), titanium oxide 2.4% blended capsule (capsule B) and titanium oxide 3.6% blended capsule (capsule C) According to the method described in Example 1, a light stability test was performed on the capsule filled in each capsule. As a control, a PTP packaged product of a capsule containing 1.2% titanium oxide (capsule A) placed in an aluminum bag and shielded from light was similarly tested.
For each capsule, before starting the test, after exposure of about 672,000 lux / hour and after exposure of about 1.2 million lux / hour, take out the contents and perform appearance observation and quantification of photodegradation products (related substances) It was. The photodegradation product was quantified by the following HPLC analysis method, and the discoloration was performed by visual observation.
光分解物（類縁物質）定量試験
被験製剤５カプセルをとり、カプセルの内容物を５０ｍＬのメスフラスコに入れた。また内容物を取出したカプセルは移動相で２回洗浄し、この時の洗浄した液は内容物を入れたメスフラスコに入れた。メスフラスコ容量の約３分の２まで移動相を加え、１５分間振とうを行った後、移動相で５０ｍＬとした。この液を０．４５μｍのメンブランフィルターでろ過し、最初のろ液２〜３ｍＬを除き、次のろ液を試料溶液とした。試料溶液２５μＬにつき、次の条件でＨＰＬＣ測定を行ない、自動積分法により各ピークの面積を求め、ＫＭＤ−３２１３ピーク面積に対する個々の類縁物質ピーク面積の百分率を算出した。
Photolytic product (related substance)
ＨＰＬＣ測定条件
測定波長：２２５ｎｍ
カラム：Ｉｎｅｒｔｓｉｌ ＯＤＳ−３（ジーエルサイエンス株式会社）
カラム温度：約２５℃
移動相：リン酸２水素ナトリウム２水塩３．９ｇおよび希リン酸水溶液（１→２０）２．５ｍＬに水を加えて全量１０００ｍＬとし、この液とアセトニトリルとの５：２混合溶液
流速：ＫＭＤ−３２１３の保持時間を約７分に調整。
面積測定範囲：約３０分間
HPLC measurement conditions Measurement wavelength: 225 nm
Column: Inertsil ODS-3 (GL Sciences Inc.)
Column temperature: about 25 ° C
Mobile phase: Water is added to 3.9 g of sodium dihydrogen phosphate dihydrate and 2.5 mL of dilute phosphoric acid aqueous solution (1 → 20) to make a total volume of 1000 mL, and a 5: 2 mixed solution of this solution and acetonitrile Flow rate: KMD -Adjusted the hold time of 3213 to about 7 minutes.
Area measurement range: about 30 minutes
結果は図５および表６に示すとおり、カプセルＡ（酸化チタン１．２％配合）では、約６７．２万ルクス／時間の曝光量でも外観および類縁物質総量において設定規格に適合せず、カプセルＢ（酸化チタン２．４％配合）では、約１２０万ルクス／時間の曝光量で設定規格限界乃至は不適合であり、カプセルＣ（酸化チタン３．６％配合）では、１２０万ルクス／時間の曝光量でも外観および類縁物質総量共に安定で、設定規格に適合した。 As shown in FIG. 5 and Table 6, the capsule A (containing 1.2% titanium oxide) does not meet the set standard in appearance and total amount of related substances even with an exposure dose of about 672,000 lux / hour. In B (titanium oxide 2.4% blending), the set standard limit or non-conformity is reached at an exposure amount of about 1.2 million lux / hour, and in capsule C (titanium oxide 3.6% blending) 1.2 million lux / hour. Appearance and total amount of related substances were stable even at exposure, and met the set standards.
本発明の経口固形医薬は、製造工程における操作性や含有量のバラツキなどの製造上の問題がなく、しかも溶出特性の優れた、実用性の高い排尿障害治療用経口固形製剤である。本発明の経口固形医薬は、カプセル剤または錠剤の充填工程あるいは打錠工程における操作性がよく、充填精度が高く、活性成分の含有量が一定であり、また、安定性もよく、活性成分の含有量の変化も少なく、さらには、最も難溶で、生物学的非同等性が最も捉えやすい水における、溶出試験において、一定で良好な溶出特性を示す、極めて優れた排尿障
害治療用経口固形製剤である。
The oral solid pharmaceutical of the present invention is a highly practical oral solid preparation for treating urination disorders that has no problems in production such as operability and content variation in the production process and has excellent dissolution characteristics. The oral solid medicine of the present invention has good operability in the capsule or tablet filling step or tableting step, has high filling accuracy, has a constant content of the active ingredient, has good stability, A very good oral solid for treatment of dysuria, with little change in content, and with constant and good dissolution characteristics in the dissolution test in water, which is the least soluble and the most readily bioinequal. It is a formulation.
Claims (14)
（２）工程（１）で得られる造粒物と、ステアリン酸マグネシウム、ステアリン酸カルシウムおよびタルクから選択される滑沢剤を混合、圧縮成形する工程を包含する、錠剤の製造方法。(2) A method for producing a tablet, comprising a step of mixing and compression-molding the granulated product obtained in step (1) and a lubricant selected from magnesium stearate, calcium stearate and talc.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2007253411A JP4805234B2 (en) | 2002-12-16 | 2007-09-28 | Oral solid medicine |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002364238 | 2002-12-16 | ||
| JP2002364238 | 2002-12-16 | ||
| JP2007253411A JP4805234B2 (en) | 2002-12-16 | 2007-09-28 | Oral solid medicine |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2004560618A Division JP4633469B2 (en) | 2002-12-16 | 2003-12-11 | Oral solid medicine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2008044960A true JP2008044960A (en) | 2008-02-28 |
| JP4805234B2 JP4805234B2 (en) | 2011-11-02 |
Family
ID=39179018
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2007253411A Expired - Lifetime JP4805234B2 (en) | 2002-12-16 | 2007-09-28 | Oral solid medicine |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP4805234B2 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013529663A (en) * | 2010-06-28 | 2013-07-22 | ラティオファルム ゲー・エム・ベー・ハー | Silodosin-cyclodextrin inclusion compound |
| WO2014157137A1 (en) | 2013-03-26 | 2014-10-02 | キッセイ薬品工業株式会社 | Oral administration preparation with masked bitterness of silodosin |
| JP2016523846A (en) * | 2013-06-06 | 2016-08-12 | フィブロジェン インコーポレイテッド | Pharmaceutical formulation of HIF prolyl hydroxylase inhibitor |
| JP2016210760A (en) * | 2015-04-28 | 2016-12-15 | 大原薬品工業株式会社 | Colored tablet containing silodosin with improved light stability |
| JP2017014151A (en) * | 2015-07-01 | 2017-01-19 | 大原薬品工業株式会社 | Dry coated tablet containing silodosin with improved light stability |
| JP2020132594A (en) * | 2019-02-22 | 2020-08-31 | 日医工株式会社 | Tablets containing silodosin |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2016138073A (en) * | 2015-01-29 | 2016-08-04 | 大原薬品工業株式会社 | Silodosin-containing tablet in which stability is improved |
| JP2019070045A (en) * | 2019-02-06 | 2019-05-09 | 大原薬品工業株式会社 | Silodosin-containing tablet in which stability is improved |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999015202A1 (en) * | 1997-09-22 | 1999-04-01 | Kissei Pharmaceutical Co., Ltd. | Remedies for dysuria resulting from prostatic hypertrophy |
| JP2000247998A (en) * | 1999-02-26 | 2000-09-12 | Kissei Pharmaceut Co Ltd | Variant of alpha 1a adrenaline receptor, measuring method using the same variant and therapeutic agent for dysuria accompanying prostatic hypertrophy |
| WO2001072710A1 (en) * | 2000-03-31 | 2001-10-04 | Nippon Shinyaku Co., Ltd. | Heterocycle derivatives and drugs |
| WO2002036577A1 (en) * | 2000-11-02 | 2002-05-10 | Nippon Shinyaku Co., Ltd. | Quinazoline derivatives and drugs |
| WO2002074341A1 (en) * | 2001-03-19 | 2002-09-26 | Nippon Shinyaku Co., Ltd. | Antipruritics |
-
2007
- 2007-09-28 JP JP2007253411A patent/JP4805234B2/en not_active Expired - Lifetime
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999015202A1 (en) * | 1997-09-22 | 1999-04-01 | Kissei Pharmaceutical Co., Ltd. | Remedies for dysuria resulting from prostatic hypertrophy |
| JP2000247998A (en) * | 1999-02-26 | 2000-09-12 | Kissei Pharmaceut Co Ltd | Variant of alpha 1a adrenaline receptor, measuring method using the same variant and therapeutic agent for dysuria accompanying prostatic hypertrophy |
| WO2001072710A1 (en) * | 2000-03-31 | 2001-10-04 | Nippon Shinyaku Co., Ltd. | Heterocycle derivatives and drugs |
| WO2002036577A1 (en) * | 2000-11-02 | 2002-05-10 | Nippon Shinyaku Co., Ltd. | Quinazoline derivatives and drugs |
| WO2002074341A1 (en) * | 2001-03-19 | 2002-09-26 | Nippon Shinyaku Co., Ltd. | Antipruritics |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2016117738A (en) * | 2010-06-28 | 2016-06-30 | ラティオファルム ゲー・エム・ベー・ハー | Silodosin-cyclodextrin inclusion compounds |
| JP2013529663A (en) * | 2010-06-28 | 2013-07-22 | ラティオファルム ゲー・エム・ベー・ハー | Silodosin-cyclodextrin inclusion compound |
| JP2018199699A (en) * | 2013-03-26 | 2018-12-20 | キッセイ薬品工業株式会社 | Preparation for oral administration in which bitter taste of silodosin is masked |
| WO2014157137A1 (en) | 2013-03-26 | 2014-10-02 | キッセイ薬品工業株式会社 | Oral administration preparation with masked bitterness of silodosin |
| JP2019137703A (en) * | 2013-06-06 | 2019-08-22 | フィブロジェン インコーポレイテッド | Pharmaceutical formulations of hif prolyl hydroxylase inhibitor |
| JP2016523846A (en) * | 2013-06-06 | 2016-08-12 | フィブロジェン インコーポレイテッド | Pharmaceutical formulation of HIF prolyl hydroxylase inhibitor |
| US10765672B2 (en) | 2013-06-06 | 2020-09-08 | Fibrogen, Inc. | Pharmaceutical formulations of a HIF hydroxylase inhibitor |
| JP2018070659A (en) * | 2015-04-28 | 2018-05-10 | 大原薬品工業株式会社 | Silodosin-containing coloring tablet having improved light stability |
| JP2018123146A (en) * | 2015-04-28 | 2018-08-09 | 大原薬品工業株式会社 | Colored tablet containing silodosin with improved light stability |
| JP2016210760A (en) * | 2015-04-28 | 2016-12-15 | 大原薬品工業株式会社 | Colored tablet containing silodosin with improved light stability |
| JP2020200348A (en) * | 2015-04-28 | 2020-12-17 | 大原薬品工業株式会社 | Colored tablet containing silodosin with improved light stability |
| JP2017014151A (en) * | 2015-07-01 | 2017-01-19 | 大原薬品工業株式会社 | Dry coated tablet containing silodosin with improved light stability |
| JP2020132594A (en) * | 2019-02-22 | 2020-08-31 | 日医工株式会社 | Tablets containing silodosin |
Also Published As
| Publication number | Publication date |
|---|---|
| JP4805234B2 (en) | 2011-11-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4633469B2 (en) | Oral solid medicine | |
| JP4805234B2 (en) | Oral solid medicine | |
| JP4868695B2 (en) | Oral preparation with good disintegration | |
| TWI564008B (en) | Formulation for solubility enhancement of poorly soluble drugs | |
| JP7116277B2 (en) | Granules, tablets and manufacturing method thereof | |
| JP5719385B2 (en) | Solid pharmaceutical formulation of ramipril and amlodipine besylate and its production | |
| KR102486126B1 (en) | Pharmaceutical compositions comprising alpelisib | |
| BR112019028278A2 (en) | pharmaceutical compositions | |
| KR20160079178A (en) | Solid Preparation Comprising Silodosin for Oral Administration | |
| CN118119380A (en) | Pharmaceutical composition | |
| CA3234841A1 (en) | Pharmaceutical compositions | |
| EP4268816A1 (en) | Oral solid preparation | |
| NZ555003A (en) | Solid drug for oral use comprising indoline compound | |
| Kadam Goving | Design and Development of Caplets Bearing Lafutidine and Domperidone | |
| JP2018012649A (en) | Tablet and method for producing the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20110405 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20110524 |
|
| A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20110527 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20110624 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20110809 |
|
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20110810 |
|
| R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 Ref document number: 4805234 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20140819 Year of fee payment: 3 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| EXPY | Cancellation because of completion of term |