CN115894340B - Crystal form A of bupivacaine meloxicam salt and single crystal, preparation method and application thereof - Google Patents
Crystal form A of bupivacaine meloxicam salt and single crystal, preparation method and application thereof Download PDFInfo
- Publication number
- CN115894340B CN115894340B CN202211281061.0A CN202211281061A CN115894340B CN 115894340 B CN115894340 B CN 115894340B CN 202211281061 A CN202211281061 A CN 202211281061A CN 115894340 B CN115894340 B CN 115894340B
- Authority
- CN
- China
- Prior art keywords
- bupivacaine
- meloxicam
- single crystal
- meloxicam salt
- salt 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.)
- Active
Links
- 229960003150 bupivacaine Drugs 0.000 title claims abstract description 104
- 239000013078 crystal Substances 0.000 title claims abstract description 85
- -1 bupivacaine meloxicam salt Chemical class 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 239000007787 solid Substances 0.000 claims abstract description 28
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 19
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 claims description 50
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 claims description 38
- 229960001929 meloxicam Drugs 0.000 claims description 30
- 239000003960 organic solvent Substances 0.000 claims description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 19
- 239000012296 anti-solvent Substances 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 238000010992 reflux Methods 0.000 claims description 11
- 208000002193 Pain Diseases 0.000 claims description 10
- 230000036407 pain Effects 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 238000002329 infrared spectrum Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
- 229940011051 isopropyl acetate Drugs 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000001757 thermogravimetry curve Methods 0.000 claims description 3
- 230000004580 weight loss Effects 0.000 claims description 3
- 238000010521 absorption reaction Methods 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims 4
- 238000004090 dissolution Methods 0.000 abstract description 11
- 238000005286 illumination Methods 0.000 abstract description 5
- 238000002844 melting Methods 0.000 abstract description 5
- 230000008018 melting Effects 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000001647 drug administration Methods 0.000 abstract description 2
- 238000003908 quality control method Methods 0.000 abstract description 2
- 238000003860 storage Methods 0.000 abstract description 2
- 238000001514 detection method Methods 0.000 description 24
- 239000000243 solution Substances 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 10
- 230000005855 radiation Effects 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 6
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 5
- 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 description 5
- 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 5
- 229930195725 Mannitol Natural products 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 238000006073 displacement reaction Methods 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 239000000594 mannitol Substances 0.000 description 5
- 235000010355 mannitol Nutrition 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 238000007789 sealing Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 4
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000001144 powder X-ray diffraction data Methods 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- 229920001710 Polyorthoester Polymers 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 206010052428 Wound Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000002050 diffraction method Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 229940049654 glyceryl behenate Drugs 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000003589 local anesthetic agent Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000002745 poly(ortho ester) Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000002076 thermal analysis method Methods 0.000 description 2
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 2
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- 108700032845 Ala(2)- enkephalinamide-Met Proteins 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Polymers OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- 206010019973 Herpes virus infection Diseases 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000029836 Inguinal Hernia Diseases 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000002847 Surgical Wound Diseases 0.000 description 1
- 206010053692 Wound complication Diseases 0.000 description 1
- 238000005162 X-ray Laue diffraction Methods 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 238000003353 bioavailability assay Methods 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229960001050 bupivacaine hydrochloride Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 210000002858 crystal cell Anatomy 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000013150 knee replacement Methods 0.000 description 1
- LEBVLXFERQHONN-INIZCTEOSA-N levobupivacaine Chemical compound CCCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-INIZCTEOSA-N 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229940106885 marcaine Drugs 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 208000013465 muscle pain Diseases 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000007779 soft material Substances 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 238000000982 solution X-ray diffraction Methods 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- JCQBWMAWTUBARI-UHFFFAOYSA-N tert-butyl 3-ethenylpiperidine-1-carboxylate Chemical group CC(C)(C)OC(=O)N1CCCC(C=C)C1 JCQBWMAWTUBARI-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pain & Pain Management (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The application relates to a crystal form A of bupivacaine meloxicam salt and a single crystal, a preparation method and application thereof. The crystalline form a of bupivacaine meloxicam salt having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ (°) angles: 7.5.+ -. 0.2, 8.3.+ -. 0.2, 12.7.+ -. 0.2, 15.1.+ -. 0.2, 16.1.+ -. 0.2, 16.6.+ -. 0.2, 24.9.+ -. 0.2 and 25.0.+ -. 0.2. The A crystal form has stable form and definite melting point, good chemical stability, high temperature resistance and high illumination, has the performance required by preparing a solid preparation, and has the advantages of higher drug administration concentration, better dissolution, better compressibility and disintegration, convenient storage, simpler production operation of the preparation and easier quality control.
Description
Technical Field
The application relates to the technical field of medicines, in particular to a crystal form A of bupivacaine meloxicam salt, a single crystal thereof, a preparation method and application.
Background
Bupivacaine (Bupivacaine) is an amide local anesthetic, the first product on the market is bupivacaine hydrochloride injection, developed and marketed by Hospira in 1972 for use in surgical, oral, diagnostic and therapeutic operations and obstetric operations, under the trade name Marcaine, and bupivacaine has therefore also been called bupivacaine. As a non-opioid, bupivacaine avoids the addictive nature of opioids, but the conventional dosing concentration of bupivacaine is 0.5%. Thus, there is an urgent need to increase the concentration of drug administered in clinic, and there is an urgent need to solve the solubility of drugs in pharmacy.
Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) and antipyretic, currently used to alleviate the symptoms of arthritis, fever, and as an analgesic for inflammatory conditions. Meloxicam was originally developed by BoehringerIngelheim and marketed in europe under the brands Melox, movalis and Recoxa for the treatment of rheumatoid arthritis, for short term use in osteoarthritis and ankylosing spondylitis. Meloxicam is commercialized as tablets, orally disintegrating tablets and capsules, 7.5 and 15 mg per dose, and 7.5 mg per 5 ml per dose of oral suspension.
The bupivacaine/meloxicam sustained-release liquid (trade name: zynrelef, development code: HTX-011) was developed by HeronTherapeutics company, was approved by FDA for marketing on day 13, 05, 2021, and was instilled around soft tissues or joints in the operation area after bunyaosteotomy, open inguinal hernia repair, and total knee replacement in adult patients, resulting in postoperative analgesia. The product is approved by European Union as early as 09 in 2020, and can be used for treating somatic postoperative pain caused by small and medium-sized surgical wounds in adults.
Zynrelef is a fixed dose combination of bupivacaine and meloxicam in a ratio of 33:1.1, wherein the lower amount of meloxicam as a non-steroidal anti-inflammatory drug (NSAID) reduces wound inflammation, relieves pain, increases the local pH of the wound, brings the pH to normal and allows more bupivacaine to penetrate the cell membrane, thereby achieving good synergistic analgesic effect.
Zynrelef is currently the only commercially available double-acting local anesthetic (Dual-actingLocal Anesthetic, DALA), but the preparation adoptsThe technology takes fourth generation polyorthoester (Polyorthoesters, POE) prepared by condensation of glycol and diketone acetal as a material, and the polyorthoester material is actually a composite material and comprises diethylene tetraoxaspiro undecane, triethylene glycol and triethylene glycol polyglycolide. The pharmaceutical stability of these novel adjuvants is to be examined and the use of DMSO as a formulation solvent is required, and further confirmation of the application in the art is also to be made.
Disclosure of Invention
Based on the above, the application provides a crystal form A of bupivacaine meloxicam salt with higher administration concentration, better dissolution and stable property, and a single crystal, a preparation method and application thereof.
In a first aspect of the present invention, there is provided a crystalline form a of bupivacaine meloxicam salt having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ (°) angles:
7.5±0.2、8.3±0.2、12.7±0.2、15.1±0.2、16.1±0.2、16.6±0.2、24.9±0.2、25.0±0.2。
2. Form a of bupivacaine meloxicam salt according to claim 1, further comprising 1 or 2 or more characteristic diffraction peaks at 2Θ (°) angles selected from: 18.9.+ -. 0.2, 10.1.+ -. 0.2, 17.3.+ -. 0.2, 18.9.+ -. 0.2, 21.0.+ -. 0.2, 25.2.+ -. 0.2.
According to a second aspect of the present invention, there is provided a process for the preparation of form a of bupivacaine meloxicam salt according to the first aspect, comprising the steps of:
Mixing bupivacaine, meloxicam and an organic solvent, heating and refluxing until the bupivacaine, meloxicam and the organic solvent are dissolved, concentrating the reaction solution until solid is separated out, adding an anti-solvent, continuously separating out the solid, collecting the solid, and drying to prepare the A crystal form of the bupivacaine meloxicam salt.
In a third aspect of the present invention, there is provided a single crystal of form a of the salt of bupivacaine of the first aspect, comprising 4 single crystal molecules of the salt of bupivacaine in a unit cell structure.
In a fourth aspect of the present invention, there is provided a pharmaceutical composition comprising one or more of the crystalline form a of bupivacaine meloxicam salt according to the first aspect and the single crystal of crystalline form a of bupivacaine meloxicam salt according to the third aspect, together with a pharmaceutically acceptable carrier and/or excipient.
According to a fifth aspect of the present invention, there is provided the use of the crystalline form a of bupivacaine meloxicam salt according to the first aspect, the single crystal of the crystalline form a of bupivacaine meloxicam salt according to the third aspect, or the pharmaceutical composition according to the fourth aspect for the manufacture of a medicament for the treatment of localized pain.
In the process of preparing the crystalline compound of the bupivacaine meloxicam salt, the inventor crystallizes the crude product of the substance by a recrystallization method to obtain a new crystal form, namely a crystal form A. The obtained crystals were confirmed to be a novel crystal, namely, form a of a crystalline compound of 1-N-butyl-2- (2, 6-dimethylcarbamoyl) piperidine and 4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1, 2-benzothiazine-3-carboxamide 1, 1-dioxide, by subjecting the crystals to detection and analysis such as X-ray powder diffraction, DSC, TG, IR, elemental analysis, etc. The A crystal form has stable form and definite melting point, good chemical stability, high temperature resistance and high illumination, has the performance required by preparing a solid preparation, and has the advantages of higher drug administration concentration, better dissolution, better compressibility and disintegration, convenient storage, simpler production operation of the preparation and easier quality control.
Meanwhile, the A crystal form also has good bioavailability in the research process.
Drawings
FIG. 1 is an X-ray diffraction pattern of form A obtained in example 1 of the present invention;
FIG. 2 is a DSC chart of form A obtained in example 1 of the present invention;
FIG. 3 is a pattern of TG in form A obtained in example 1 of the present invention;
FIG. 4 is an IR spectrum of form A obtained in example 1 of the present invention;
FIG. 5 is an HPLC chart of form A obtained in example 1 of the present invention;
FIG. 6 is a comparative graph of the stability test of form A obtained in example 1 of the present invention;
FIG. 7 is a graph comparing the bioavailability of bupivacaine in animals of form A obtained in example 1 of the present invention;
FIG. 8 is a crystal morphology of a single crystal obtained in example 20 of the present invention;
FIG. 9 is a molecular structure and atomic number (club diagram) of a single crystal obtained in example 20 of the present invention;
FIG. 10 is a molecular structure and atomic number (line pattern) of a single crystal obtained in example 20 of the present invention;
FIG. 11 is a unit cell structure (in atomic scale) of the single crystal obtained in example 20 of the present invention;
FIG. 12 is a unit cell structure (in symmetry) of the single crystal obtained in example 20 of the present invention;
FIG. 13 is an absolute configuration of a single crystal (wherein black C is a chiral C atom) obtained in example 20 of the present invention.
Detailed Description
The form a of bupivacaine meloxicam salt and its single crystals, preparation method and application according to the present application are described in further detail below with reference to specific examples. The present application may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein in the description of the application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.
Herein, "one or more" refers to any one, any two, or any two or more of the listed items.
In the present application, "first aspect", "second aspect", "third aspect", "fourth aspect", etc. are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or quantity, nor as implying an importance or quantity of technical features indicated. Moreover, the terms "first," "second," "third," "fourth," and the like are used for non-exhaustive list description purposes only, and are not to be construed as limiting the number of closed forms.
In the application, the technical characteristics described in an open mode comprise a closed technical scheme composed of the listed characteristics and also comprise an open technical scheme comprising the listed characteristics.
In the present application, the numerical ranges are referred to as continuous, and include the minimum and maximum values of the ranges, and each value between the minimum and maximum values, unless otherwise specified. Further, when a range refers to an integer, each integer between the minimum and maximum values of the range is included. Further, when multiple range description features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to include any and all subranges subsumed therein.
The percentage content referred to in the present application refers to mass percentage for both solid-liquid mixing and solid-solid mixing and volume percentage for liquid-liquid mixing unless otherwise specified.
The percentage concentrations referred to in the present application refer to the final concentrations unless otherwise specified. The final concentration refers to the ratio of the additive component in the system after the component is added.
The temperature parameter in the present application is not particularly limited, and may be a constant temperature treatment or a treatment within a predetermined temperature range. The constant temperature process allows the temperature to fluctuate within the accuracy of the instrument control.
Room temperature in the present application generally means 4 ℃ to 30 ℃, preferably 22 ℃ to 27 ℃.
The application relates to a salt of bupivacaine meloxicam, which is generated by the reaction of bupivacaine and meloxicam and has the following structural characteristics:
the chemical name of the bupivacaine meloxicam salt is 4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1, 2-benzothiazine-3-carboxamide 1, 1-dioxide and 1-N-butyl-2- (2, 6-dimethylcarbamoyl) piperidine.
The application provides a crystal form A of bupivacaine meloxicam salt, which has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 theta (DEG) angles:
7.5.+ -. 0.2, 8.3.+ -. 0.2, 12.7.+ -. 0.2, 15.1.+ -. 0.2, 16.1.+ -. 0.2, 16.6.+ -. 0.2, 24.9.+ -. 0.2 and 25.0.+ -. 0.2.
The radiation source used in the X-ray powder diffraction pattern is, without limitation, cu radiation source. The X-ray powder diffraction pattern refers to a PXRD pattern.
Further, the X-ray powder diffraction pattern of form a has characteristic diffraction peaks at the following 2θ (°) angles:
7.5.+ -. 0.1, 8.3.+ -. 0.1, 12.7.+ -. 0.1, 15.1.+ -. 0.1, 16.1.+ -. 0.1, 16.6.+ -. 0.1, 24.9.+ -. 0.1 and 25.0.+ -. 0.1.
Further, the relative intensities (I/I 0) of the characteristic diffraction peaks are all greater than or equal to 30%.
In one example, the form a further comprises 1 or 2 or more characteristic diffraction peaks at 2θ (°) angles selected from: 18.9.+ -. 0.2, 10.1.+ -. 0.2, 17.3.+ -. 0.2, 18.9.+ -. 0.2, 21.0.+ -. 0.2 and 25.2.+ -. 0.2.
The radiation source used in the X-ray powder diffraction pattern is, without limitation, cu radiation source. The X-ray powder diffraction pattern refers to a PXRD pattern.
Further, the form a further comprises 1 or 2 or more characteristic diffraction peaks at 2θ (°) angles selected from: 18.9.+ -. 0.1, 10.1.+ -. 0.1, 17.3.+ -. 0.1, 18.9.+ -. 0.1, 21.0.+ -. 0.1 and 25.2.+ -. 0.1.
Further, the relative intensities (I/I 0) of the characteristic diffraction peaks are all 20% or more.
In one example, the form a further comprises 1 or 2 or more characteristic diffraction peaks at 2θ (°) angles selected from: 18.1.+ -. 0.2, 20.2.+ -. 0.2, 22.7.+ -. 0.2, 23.8.+ -. 0.2, 24.0.+ -. 0.2, 25.8.+ -. 0.2, 26.4.+ -. 0.2 and 26.5.+ -. 0.2.
The radiation source used in the X-ray powder diffraction pattern is, without limitation, cu radiation source. The X-ray powder diffraction pattern refers to a PXRD pattern.
Further, the form a further comprises 1 or 2 or more characteristic diffraction peaks at 2θ (°) angles selected from: 18.1.+ -. 0.1, 20.2.+ -. 0.1, 22.7.+ -. 0.1, 23.8.+ -. 0.1, 24.0.+ -. 0.1, 25.8.+ -. 0.1, 26.4.+ -. 0.1 and 26.5.+ -. 0.1.
Further, the relative intensities (I/I 0) of the characteristic diffraction peaks are all 10% or more.
In one example, the main parameters of the X-ray powder diffraction pattern of form a of the form a are as follows:
where the relative intensity values are close values, "close" refers to the uncertainty of the intensity measurement, and one skilled in the art understands that the uncertainty of the relative intensity is related to the measurement conditions and may vary, for example, within a range of + -25% or preferably within a range of + -10%.
In one example, the form a has an X-ray powder diffraction pattern substantially as shown in figure 1. The radiation source used in the X-ray powder diffraction pattern is, without limitation, cu radiation source. The X-ray powder diffraction pattern refers to a PXRD pattern.
In one example, the differential scanning calorimetry curve of form a has an endothermic peak at 189.6 ℃ ± 3 ℃. Further, the differential scanning calorimetry curve of the form a has an endothermic peak at 189.6 ℃ ± 1 ℃.
In one example, the differential scanning calorimetric curve of form a is substantially as shown in fig. 2.
In one example, the thermogram of form a has a 57% ± 1% weight loss in the range of 210 ℃ to 300 ℃.
In one example, the thermogram of form a is substantially as shown in fig. 3. Meanwhile, thermogravimetric spectra (TGA) showed a weight loss of 0.4% ± 1% in the range of 50 ℃ to 150 ℃, which is a loss caused by solvent residue.
In one example, the infrared spectrum of form a includes the following absorption peaks:
3436cm-1、3291cm-1、2960cm-1、1690cm-1、1603cm-1、1549cm-1、1522cm-1、1456cm-1、1395cm-1、1337cm-1、1233cm-1、1188cm-1、1169cm-1、1125cm-1、1067cm-1、941cm-1、861cm-1、768cm-1、741cm-1、619cm-1、574cm-1、524cm-1 And 464cm -1.
In one example, the infrared spectrum of form a is substantially as shown in fig. 4.
The application also provides a preparation method of the A crystal form of the bupivacaine meloxicam salt, which comprises the following steps:
Mixing bupivacaine, meloxicam and an organic solvent, heating and refluxing until the bupivacaine, meloxicam and the organic solvent are dissolved, concentrating the reaction solution until solid is separated out, adding an anti-solvent, continuously separating out the solid, collecting the solid, and drying to prepare the A crystal form of the bupivacaine meloxicam salt.
In one example, the organic solvent is one or more of butanone, acetone, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, ethyl acetate, and isopropyl acetate; further, the organic solvent is acetone.
In one example, the anti-solvent is one or more of water, isopropanol, and n-heptane. Further, the antisolvent is water.
In one example, the volume ratio of the organic solvent to the antisolvent is 1-4:1. Further, the volume ratio of the organic solvent to the antisolvent is 1.5-2.5:1.
In one example, the molar ratio of meloxicam to bupivacaine is 1:1 to 5. Further, the molar ratio of meloxicam to bupivacaine is 1:1-2.
In one example, the ratio between the total mass of bupivacaine and meloxicam and the total volume of the organic solvent and antisolvent is from 5mg to 20mg to 1ml. Further, the ratio is 7mg to 11mg to 1mL.
In one example, the temperature of the heated reflux is 30 ℃ to 80 ℃. Further, the temperature of the heating reflux is 58-62 ℃.
In one example, the time to continue to precipitate solids is 2 to 8 hours. Further, the time for continuing to precipitate the solid is 3 to 5 hours.
In one example, the temperature at which solids continue to precipitate is 0 to 40 ℃. Further, the temperature at which the solid is continuously precipitated is 20 to 30 ℃.
In one example, the temperature of drying is 30 ℃ to 60 ℃. Further, the drying temperature is 45-55 ℃.
In one example, the temperature of concentration is 40℃to 50℃and the pressure is-0.2 MPa to-0.1 MPa.
The application also provides a single crystal of form a of the salt of bupivacaine as described above, having a unit cell structure in which one unit cell comprises 4 single crystal molecules of the salt of bupivacaine.
In one example, in the single crystal unit cell structure, the independent symmetry elements are double helical axes and n slip planes.
In one example, the crystallographic structural parameters of the single crystal are as follows:
The application also provides a preparation method of the single crystal of the A crystal form of the bupivacaine meloxicam salt, which comprises the following steps:
Mixing bupivacaine, meloxicam and an organic solvent, heating and refluxing until the bupivacaine, meloxicam and the organic solvent are dissolved, volatilizing the organic solvent in the reaction liquid until solids are separated out, and collecting the solids to prepare the single crystal.
In one example, the organic solvent is one or more of butanone, acetone, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, ethyl acetate, and isopropyl acetate. Further, the organic solvent is acetone.
In one example, the molar ratio of meloxicam to bupivacaine is 1:1 to 5. Further, the molar ratio of meloxicam to bupivacaine is 1:1-2.
In one example, the ratio between the total mass of bupivacaine and meloxicam and the volume of the organic solvent is 5mg to 20mg to 1ml. Further, the ratio is 7mg to 11mg to 1mL.
In one example, the temperature of the heated reflux is 30 ℃ to 80 ℃; further, the temperature of the heating reflux is 58-62 ℃.
In one example, volatilizing the organic solvent in the reaction solution includes the steps of: and placing the reaction liquid in a glass bottle, sealing the reaction liquid by a sealing layer, and arranging a vent hole on the sealing layer. The sealing layer is, without limitation, a sealing film.
Further, the vent holes are 1-2 holes pricked by the needle of a 10mL syringe.
In one example, the organic solvent in the reaction solution is volatilized for 2 to 10 days at room temperature.
The application also provides a pharmaceutical composition comprising one or more of the crystal form a of the bupivacaine meloxicam salt as described above and the single crystal form a of the bupivacaine meloxicam salt as described above, and a pharmaceutically acceptable carrier and/or excipient.
It will be appreciated that the above pharmaceutical compositions may be further formulated in a form for administration, including oral or parenteral administration, according to conventional formulation methods. In a pharmaceutically acceptable form, a therapeutically effective amount of the crystalline form a of bupivacaine meloxicam salt and/or a single crystal of the crystalline form a of bupivacaine meloxicam salt should be included. By "therapeutically effective amount" is meant that at this dose, the crystalline form a of bupivacaine meloxicam salt and the single crystals of the crystalline form a of bupivacaine meloxicam salt according to the invention not only have improved therapeutic activity for pain relief, but also exhibit greatly improved solubility when used for parenteral administration and greatly improved transdermal permeability when used for topical treatment.
Without limitation, the pharmaceutical composition is suitable for use in topical treatment in a formulation format including, but not limited to, solutions, gels, milk gels, creams, ointments, lotions, skin patches or eye drops. The pharmaceutical composition is also suitable for parenteral injection.
The application also provides application of the pharmaceutical composition in preparation of medicines with effects of treating local pain. Such localized pain includes, but is not limited to, muscle pain, joint pain, pain associated with herpes infections, wound pain (such as surgical pain or burn pain), and the like.
The pharmaceutical composition of the application is particularly suitable for use in the treatment of patients with localized pain. Without limitation, it is by topical and parenteral treatment of these patients with an effective amount of the pharmaceutical formulation.
The following are specific examples.
Meloxicam, bupivacaine and other agents referred to in the examples are all commercially available.
Test conditions for example samples:
PXRD (first):
detection instrument: rigaku SmartLab SE A
Detection conditions: the voltage of the X-ray tube is 40kV, the current of the X-ray tube is 40mA, the scanning range is 3-40 degrees (2 theta), the step size is 0.02 degrees, and the scanning speed is 5 degrees/min.
The detection basis is as follows: account IX FX ray powder diffraction method of the people's republic of China (second edition 2020)
Detection result: as in fig. 1.
(II) DSC
Detection instrument: relaxation-resistant STA449F3
Detection conditions: nitrogen, 50mL/min
Scanning procedure: 30-350 ℃, and the temperature rising rate is as follows: 10 ℃/min
Detecting the mass of a sample: 2.906mg (alumina sample tray)
The detection basis is as follows: JY/T014-1996 thermal analysis method general rule
Detection result: as in fig. 2.
(III) TGA
Detection instrument: relaxation-resistant STA 449F3
Detection conditions: nitrogen, 50mL/min
Scanning procedure: 30-350 ℃, and the temperature rising rate is as follows: 10 ℃/min
Detecting the mass of a sample: 1.68mg (alumina sample tray)
The detection basis is as follows: JY/T014-1996 thermal analysis method general rule
Detection result: as in fig. 3.
(IV) Infrared Spectrum
Detection instrument: PE Fourier transform infrared microscope system (Spotlight 200 i)
Detection conditions: potassium bromide tabletting method
The detection basis is as follows: GB/T6040-2002 infrared spectrum analysis method general rule
Detection result: as in fig. 4.
(V) HPLC
Detection instrument: WATERS ALLIANCE E2695,995
Chromatographic column: reverse C18 liquid chromatographic column (octadecylsilane chemically bonded silica is used as filler)
Column temperature: 30 DEG C
Mobile phase: methanol-0.1 mol/L ammonium acetate solution (1:1)
Detection wavelength: 270nm
Detection result: as in fig. 5.
(Six) SXRD
Detection instrument: bruker D8 VENTURE double micro focal spot single crystal X-ray diffractometer
Detection conditions: ambient temperature 193K, enhanced Cu light source, wavelength
The detection basis is as follows: JY/T0588-2020 general rules of analysis methods for measuring crystals and molecular structures of small molecular compounds by single crystal X-ray diffractometer
Detection result: as shown in fig. 8-13.
Preparation of crystalline compound A of 1-N-butyl-2- (2, 6-dimethylcarbamoyl) piperidine and 4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1, 2-benzothiazine-3-carboxamide 1, 1-dioxide
Example 1 preparation of crystalline form a of bupivacaine/meloxicam salt by means of a solution crystallization process.
10G of meloxicam and 8.2g of bupivacaine were added to 2L of acetone (organic solvent), heated to reflux at 60℃and stirred to dissolve completely. Concentrating the clear solution under reduced pressure (45 ℃ and minus 0.1 MPa) until solid is precipitated, stopping concentrating, adding 1L of n-heptane (anti-solvent) and stirring at 25 ℃ (solid precipitation temperature) for 4 hours (solid precipitation time), filtering, and vacuum drying the solid sample at 50 ℃ (drying temperature) for 12 hours to obtain the bupivacaine meloxicam salt A crystal form. 15.8g of pale yellow solid powder, and the mass yield is 86.5%.
The identification of the compound properties is shown in FIGS. 1 to 5.
Examples 2 to 16
10G of meloxicam and 8.2g of bupivacaine were added to the reaction flask, and the experiment was carried out in the same manner as in example 1, while changing the parameters as shown in Table 1 below:
TABLE 1
Example 17
The stability of the crystalline form a of bupivacaine meloxicam salt of example 1 was examined under conditions of high temperature (50 ℃) and light and acceleration (40 ℃,75% rh), and samples were taken for 5 days and 10 days, respectively, and PXRD and HPLC measurements were performed, and the results are shown in table 2 and fig. 6. The results show that the bupivacaine meloxicam salt A crystal form is stable when the water content, the purity and the crystal form are compared with the data of 0 day under the conditions of high temperature, illumination and acceleration.
Table 2 results of the stability test of bupivacaine/meloxicam salt form a
EXAMPLE 18 preparation of solid pharmaceutical preparation
Prescription 1:
| Composition of the components | Dosage of |
| Crystal form A of bupivacaine meloxicam salt (example 1) | 10mg |
| Mannitol (mannitol) | 108mg |
| Lactose and lactose | 50mg |
| Crosslinked povidone | 6mg |
| Micro powder silica gel | 3mg |
| Glyceryl behenate | 3mg |
| Total amount of | 180mg |
The preparation method comprises the following steps: the above components are mixed according to a conventional preparation method and directly compressed into tablets.
Prescription 2:
| Composition of the components | Dosage of |
| Crystal form A of bupivacaine meloxicam salt (example 1) | 10g |
| Mannitol (mannitol) | 80g |
| Lactose and lactose | 65g |
| Crosslinked povidone | 15g |
| Micro powder silica gel | 5g |
| Glyceryl behenate | 5g |
| 3％HPMC | Proper amount of |
| Total amount of | 180g |
The preparation method comprises the following steps: uniformly mixing the bupivacaine meloxicam salt A crystal form of the example 1 with mannitol, lactose and crospovidone according to an equivalent multiplication method, adding a pre-prepared HPMC solution to prepare a soft material, granulating by a 20-mesh sieve, drying at 60 ℃ for 30 minutes, sieving by a 18-mesh sieve, granulating, adding aerosil, and filling into a No. 2 capsule.
Control formula:
the preparation method comprises the following steps: the above components are mixed according to a conventional preparation method and directly compressed into tablets.
Example 19 influence factor control test
According to the preparation method, 3 batches of samples are prepared according to the processes of prescriptions 1-2 and comparative prescriptions in the embodiment 18, after basic project inspection is qualified, illumination, high temperature and high humidity tests are respectively carried out, and the appearance property, content and dissolution of the samples are inspected, so that the results of influence factors show that the samples are stable in properties under the conditions of high temperature and illumination, and can be used as reference prescriptions and processes of preparations.
The dissolution rate, the compressibility and the disintegration of the prescriptions 1-2 and the comparison prescriptions are tested, and the dissolution rate testing method is a first method or a second method of < dissolution rate and release rate measuring method 0931> in the fourth part of the Chinese pharmacopoeia 2020 edition; the disintegration test method is < disintegration time limit check method 0921> in the fourth part of China pharmacopoeia 2020 edition; the compressibility is generally determined by whether or not the appearance of the tablet is cracked, covered, or hard.
The test results are shown in table 3 below:
TABLE 3 Table 3
| Investigation index | Prescription 1 | Prescription 2 | Contrast prescription |
| Dissolution rate | Good (good) | Good (good) | Difference of difference |
| Compressibility of | Good (good) | / | Preferably, it is |
| Degree of disintegration | Good (good) | Preferably, it is | Difference of difference |
According to the dissolution test of 2020 edition pharmacopoeia, the dissolution rate of the prescription 1-2 in 15 minutes is over 80 percent. The dissolution rate of the comparative prescription is only 70% in 15 minutes, and meanwhile, the compressibility and the disintegration rate are better than those of the comparative prescription.
Meanwhile, the crystalline form A of bupivacaine meloxicam salt has a melting point of 189.6 ℃ and bupivacaine has a melting point of 106 to 110 ℃, and the solubility of bupivacaine meloxicam salt A and bupivacaine melongene has the following difference in table 4:
TABLE 4 Table 4
| Solvent(s) | Bupivacaine solubility | Solubility of bupivacaine/meloxicam salt form A |
| H2O | <1mg/ml | >1.5mg/ml |
| EtOH | <1mg/ml | >1.5mg/ml |
| MeOH | <1mg/ml | >1.7mg/ml |
| IPA | <1mg/ml | <1mg/ml |
| Acetone | >1.6mg/ml | >4.0mg/ml |
| ACN | <1mg/ml | >1.7mg/ml |
| MTBE | <1mg/ml | <1mg/ml |
| 1，4-Dioxane | >1.6mg/ml | >1.1mg/ml |
| DMF | >35mg/ml | >100mg/ml |
| EA | <1mg/ml | <1mg/ml |
| DMSO | >52mg/ml | >100mg/ml |
| DMA | >52mg/ml | >100mg/ml |
| NMP | >51mg/ml | >100mg/ml |
| Toluene | <1mg/ml | <1mg/ml |
Therefore, compared with a single product of bupivacaine, the crystal form A of the bupivacaine meloxicam salt disclosed by the application has the advantages of better investigation indexes such as dissolution rate, compressibility, disintegration and the like of the preparation, and differences in the aspects of melting point, solubility, crystal solubility and the like.
EXAMPLE 20 bioavailability assay
The bupivacaine and bupivacaine meloxicam salt A crystal form and bupivacaine of example 1 are respectively administered by intragastric administration to rats at a dose of 1.5 mg/kg; each group of animals was plasma taken at different time points (0, 0.0833, 0.25, 0.5, 1,2,3, 4, 6, 8, 12, 24, 30, 48 hours) and blood concentrations were measured at the different time points.
The test results are shown in table 5 and fig. 7 below:
TABLE 5
The results show that the bioavailability of the bupivacaine meloxicam salt A crystal form in animal bodies is obviously improved, and the AUC of the bupivacaine meloxicam salt A crystal form is about 10 times that of bupivacaine, thus having quite obvious pharmacokinetic behavior improvement effect.
EXAMPLE 21 Bubicaine/meloxicam salt single crystal culture
20Mg of meloxicam and 16.4mg of bupivacaine are added into 4mL of acetone, the mixture is heated to 60 ℃ to be completely dissolved, the clear solution is placed into a glass bottle, and the mixture is subjected to hole punching and volatilization for 48 hours at 25 ℃ to obtain single crystals of the meloxicam salt A crystal form of the bupivacaine, which are light yellow rod-shaped crystals, and the crystal morphology is shown in figure 8.
The obtained single crystal is subjected to X-ray single crystal diffraction analysis to obtain a crystallographic data table and a structural diagram
The basic structure is as follows:
the molecular structure in the unit cell of the single crystal of bupivacaine meloxicam salt is presented for fig. 9 and 10, where each atom number in the molecule is identified and hydrogen is not numbered for clarity. For ease of description, the present application refers to each atom by atomic number in the figures.
Unit cell structure:
The crystal cell structure is presented for fig. 11 and 12, with 4 single crystal molecules of bupivacaine/meloxicam salt in one cell. The independent symmetrical elements in the crystal are double helical axes and n slip planes.
Absolute configuration
The absolute configuration represents the real arrangement relation of each group in the chiral molecule in space, namely the absolute spatial relation. Figure 13 shows the absolute configuration of the single crystal molecules of bupivacaine meloxicam salt within the unit cell, each single crystal molecule of bupivacaine meloxicam salt comprising 1 chiral carbon atom (black label) with an absolute configuration of C24 (R).
Specifically, the crystal data of the bupivacaine meloxicam salt single crystal are shown in tables 6 to 13:
TABLE 6 crystallographic structural parameters
TABLE 7 atomic coordinates (. Times.10 4) and equivalent isotropic Displacement parameters
TABLE 8 bond length and bond angle of bonded atoms
TABLE 9 bond angles and bond lengths of bonded atoms
TABLE 10 Anisotropic displacement factor index
Note that: form of anisotropic displacement factor index: -2pi [ h 2 a*2U11+...+2h k a*b*U 12 ], wherein a, b, c are unit lengths of the reciprocal lattice; u 11、U22、U33、U23、U13 and U 12 are anisotropic displacement parameters, which are also called temperature factors; h. k and l are diffraction indexes; parallel X-rays are directed to a perfectly sized single crystal, and diffraction occurs when the optical path difference satisfies an integer multiple of the conditional wavelength.
According to the three-dimensional laue equation:
a(cosα0-cosα)＝hλ
b(cosβ0-cosβ)＝kλ
c(cosγ0-cosγ)＝lλ
h. k and l are integers, and a group of h, k and l are called diffraction indexes, which define a specific diffraction direction.
TABLE 11 Hydrogen atom coordinates (. Times.10 4) and equivalent isotropic Displacement parameters
Table 12 Single crystal torsion angle (°)
TABLE 13 Hydrogen bonding
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples merely illustrate a few embodiments of the present application, which are convenient for a specific and detailed understanding of the technical solutions of the present application, but should not be construed as limiting the scope of the claims. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the application, which are all within the scope of the application. It should be understood that, based on the technical solutions provided by the present application, those skilled in the art may obtain technical solutions through logical analysis, reasoning or limited experiments, which are all within the scope of protection of the appended claims. The scope of the patent is therefore intended to be covered by the appended claims, and the description and drawings may be interpreted as illustrative of the contents of the claims.
Claims (12)
1. A crystalline form a of bupivacaine meloxicam salt having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ (°) angles:
7.5±0.2、8.3±0.2、10.1±0.2、12.7±0.2、15.1±0.2、16.1±0.2、16.6±0.2、17.3±0.2、18.1±0.2、18.9±0.2、20.2±0.2、21.0±0.2、22.7±0.2、23.8±0.2、24.0±0.2、24.9±0.2、25.0±0.2、25.2±0.2、25.8±0.2、26.4±0.2 And 26.5.+ -. 0.2.
2. Form a of bupivacaine meloxicam salt according to claim 1, characterized in that the X-ray powder diffraction pattern of form a is substantially as shown in figure 1.
3. Form a of bupivacaine meloxicam salt according to any of claims 1 to 2, characterized in that the differential scanning calorimetry curve of form a has an endothermic peak at 189.6 ℃ ± 3 ℃.
4. The crystalline form a of bupivacaine meloxicam salt according to any one of claims 1 to 2, characterized in that the thermogram of the crystalline form a has a weight loss of 57% ± 1% in the range of 210 ℃ to 300 ℃.
5. Form a of bupivacaine meloxicam salt according to any one of claims 1 to 2, characterized in that the infrared spectrum of form a comprises the following absorption peaks:
3436cm-1、3291cm-1、2960cm-1、1690cm-1、1603cm-1、1549cm-1、1522cm-1、1456cm-1、1395cm-1、1337cm-1、1233cm-1、1188cm-1、1169cm-1、1125cm-1、1067cm-1、941cm-1、861cm-1、768cm-1、741cm-1、619cm-1、574cm-1、524cm-1 And 464cm -1.
6. A process for the preparation of form a of bupivacaine meloxicam salt according to any one of claims 1 to 5, comprising the steps of:
Mixing bupivacaine, meloxicam and an organic solvent, heating and refluxing until the bupivacaine, meloxicam and the organic solvent are dissolved, concentrating the reaction solution until solid is separated out, adding an anti-solvent, continuously separating out the solid, collecting the solid, and drying to prepare an A crystal form of the bupivacaine meloxicam salt;
the organic solvent is one or more of butanone, acetone, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, ethyl acetate and isopropyl acetate;
The antisolvent is one or more of water, isopropanol and n-heptane;
The volume ratio of the organic solvent to the antisolvent is 1-4:1;
the molar ratio of meloxicam to bupivacaine is 1:1-5;
the ratio between the total mass of the bupivacaine and meloxicam and the total volume of the organic solvent and the antisolvent is 7 mg-20 mg:1mL;
the temperature of heating reflux is 30-80 ℃;
The time for continuously precipitating the solid is 2-8 hours;
the temperature for continuously precipitating the solid is 0-40 ℃;
The drying temperature is 30-60 ℃.
7. The process for the preparation of form a of bupivacaine meloxicam salt according to claim 6, characterized by one of the following features:
(1) The organic solvent is acetone;
(2) The antisolvent is water;
(3) The volume ratio of the organic solvent to the antisolvent is 1.5-2.5:1;
(4) The molar ratio of meloxicam to bupivacaine is 1:1-2;
(5) The ratio between the total mass of the bupivacaine and meloxicam and the total volume of the organic solvent and the antisolvent is 7 mg-11 mg:1mL;
(6) The temperature of heating reflux is 58-62 ℃;
(7) The time for continuously precipitating the solid is 3-5 hours;
(8) The temperature for continuously precipitating the solid is 20-30 ℃;
(9) The drying temperature is 45-55 ℃;
(10) The concentration temperature is 40-50 deg.c and the pressure is-0.2 MPa to-0.1 MPa.
8. A single crystal form a of bupivacaine meloxicam salt according to any one of claims 1 to 5, characterized in that in the unit cell structure of the single crystal, one unit cell comprises 4 single crystal molecules of bupivacaine meloxicam salt.
9. The single crystal of form a of bupivacaine meloxicam salt according to claim 8, wherein the independent symmetry elements in the unit cell structure of the single crystal are double helical axis and n slip plane.
10. Single crystal of form a of bupivacaine meloxicam salt according to claim 8 or 9, characterized in that the crystallographic structural parameters of the single crystal are as follows:
11. A pharmaceutical composition comprising one or more of the crystalline form a of bupivacaine meloxicam salt according to any one of claims 1 to 5 and the single crystal of crystalline form a of bupivacaine meloxicam salt according to any one of claims 8 to 10, together with a pharmaceutically acceptable carrier and/or excipient.
12. Use of a crystalline form a of bupivacaine meloxicam salt according to any one of claims 1 to 5, a single crystal of a crystalline form a of bupivacaine meloxicam salt according to any one of claims 8 to 10 or a pharmaceutical composition according to claim 11 for the preparation of a medicament having an effect of treating localized pain.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211281061.0A CN115894340B (en) | 2022-10-19 | 2022-10-19 | Crystal form A of bupivacaine meloxicam salt and single crystal, preparation method and application thereof |
| PCT/CN2023/120714 WO2024082917A1 (en) | 2022-10-19 | 2023-09-22 | Crystal form a of bupivacaine-meloxicam salt, single crystal thereof, preparation method therefor and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211281061.0A CN115894340B (en) | 2022-10-19 | 2022-10-19 | Crystal form A of bupivacaine meloxicam salt and single crystal, preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115894340A CN115894340A (en) | 2023-04-04 |
| CN115894340B true CN115894340B (en) | 2024-07-16 |
Family
ID=86487422
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211281061.0A Active CN115894340B (en) | 2022-10-19 | 2022-10-19 | Crystal form A of bupivacaine meloxicam salt and single crystal, preparation method and application thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN115894340B (en) |
| WO (1) | WO2024082917A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115894340B (en) * | 2022-10-19 | 2024-07-16 | 加立(深圳)生物科技有限公司 | Crystal form A of bupivacaine meloxicam salt and single crystal, preparation method and application thereof |
| CN118090983B (en) * | 2024-04-26 | 2024-09-06 | 山东齐都药业有限公司 | Method for detecting active substances in bupivacaine/meloxicam recovery prescription gel |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110117250A (en) * | 2018-02-06 | 2019-08-13 | 四川科伦药物研究院有限公司 | A kind of preparation method of Bupivacaine crystal form |
| CN113827547A (en) * | 2020-06-23 | 2021-12-24 | 南京清普生物科技有限公司 | Sustained-release preparation composition |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102007030695A1 (en) * | 2007-07-01 | 2009-01-08 | Sciconcept Gmbh | Co-crystal, useful e.g. to prepare a pharmaceutical formulation for the treatment of psychosis, neurological disorder and struma lymphomatosa, comprises an amino compound and urea as further component |
| EP2244712B1 (en) * | 2008-01-22 | 2015-08-05 | Thar Pharmaceuticals Inc. | In vivo studies of crystalline forms of meloxicam |
| EP2123626A1 (en) * | 2008-05-21 | 2009-11-25 | Laboratorios del Dr. Esteve S.A. | Co-crystals of duloxetine and co-crystal formers for the treatment of pain |
| WO2020095316A1 (en) * | 2018-11-05 | 2020-05-14 | Mylan Laboratories Limited | Meloxicam co-crystals |
| CN111747947A (en) * | 2020-07-30 | 2020-10-09 | 山东第一医科大学(山东省医学科学院) | Meloxicam-urea eutectic crystal and preparation method thereof |
| CN115894340B (en) * | 2022-10-19 | 2024-07-16 | 加立(深圳)生物科技有限公司 | Crystal form A of bupivacaine meloxicam salt and single crystal, preparation method and application thereof |
| CN116041342B (en) * | 2022-12-30 | 2024-02-20 | 加立(深圳)生物科技有限公司 | Crystal form I of ropivacaine/meloxicam salt monohydrate, pharmaceutical composition, preparation method and application thereof |
-
2022
- 2022-10-19 CN CN202211281061.0A patent/CN115894340B/en active Active
-
2023
- 2023-09-22 WO PCT/CN2023/120714 patent/WO2024082917A1/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110117250A (en) * | 2018-02-06 | 2019-08-13 | 四川科伦药物研究院有限公司 | A kind of preparation method of Bupivacaine crystal form |
| CN113827547A (en) * | 2020-06-23 | 2021-12-24 | 南京清普生物科技有限公司 | Sustained-release preparation composition |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2024082917A1 (en) | 2024-04-25 |
| CN115894340A (en) | 2023-04-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN115894340B (en) | Crystal form A of bupivacaine meloxicam salt and single crystal, preparation method and application thereof | |
| TWI588145B (en) | Noribogaine salt ansolvates | |
| CN116041342B (en) | Crystal form I of ropivacaine/meloxicam salt monohydrate, pharmaceutical composition, preparation method and application thereof | |
| CN110494423B (en) | Novel crystal form of lenvatinib mesylate and preparation method thereof | |
| CN110088088B (en) | Novel crystal form of { [5- (3-chlorphenyl) -3-hydroxypyridine-2-carbonyl ] amino } acetic acid and preparation method thereof | |
| WO2022121670A1 (en) | Crystal form of tolebrutinib, preparation method therefor and use thereof | |
| AU2017336889B2 (en) | Polymorphic form of kinase inhibitor compound, pharmaceutical composition containing same, and preparation method therefor and use thereof | |
| WO2017107972A1 (en) | Novel crystalline form of selective s1p1 receptor agonist and method for preparing same | |
| CN102351857A (en) | Tropiseiron hydrochloride compound | |
| CN110799501B (en) | Crystal form of orexin receptor antagonist and preparation method and application thereof | |
| US10208065B2 (en) | Crystalline free bases of C-Met inhibitor or crystalline acid salts thereof, and preparation methods and uses thereof | |
| CN110078780B (en) | Preparation method and application of progesterone eutectic | |
| JP2020500912A (en) | Crystal Form of Bromodomain Protein Inhibitor, Production Method and Use Thereof | |
| CN110944982A (en) | Crystal form of ozapimod hydrochloride and preparation method thereof | |
| CN112770756A (en) | Udacetitinib crystal form and preparation method and application thereof | |
| CN109400598B (en) | Eutectic crystal of berberine hydrochloride and lactic acid, preparation method and application thereof | |
| WO2023193563A1 (en) | Crystal form a of thienopyridine compound, and preparation method therefor and pharmaceutical composition thereof | |
| US10947185B2 (en) | Crystal form of dezocine and preparation method therefor | |
| WO2004076460A1 (en) | Method for preparing polymorphism of irinotecan hydrochloride | |
| WO2016078587A1 (en) | Lu ae58054 hydrochloride crystalline form a, and preparation method and application thereof | |
| KR101285050B1 (en) | Crystalline 1h-imidazo[4,5-b]pyridin-5-amine,7-[5-[(cyclohexylmethylamino)-methyl]-1h-indol-2-yl]-2-methyl, sulfate (1:1), trihydrate and its pharmaceutical uses | |
| CN108948018B (en) | Benzodiazepine derivatives, their salts and related crystalline forms, preparation and use | |
| WO2020011257A1 (en) | COMPOSITION OF FUSED TRICYCLIC γ-AMINO ACID DERIVATIVE AND PREPARATION THEREFOR | |
| WO2020072860A1 (en) | Niraparib solid state form | |
| WO2023078424A1 (en) | Crystal form of kras mutant inhibitor, preparation method therefor, and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |