CN114344306A - Pharmaceutical composition containing phenylpyrimidinone hydrochloride, pharmaceutical preparation containing same, and preparation method and application of pharmaceutical composition - Google Patents
Pharmaceutical composition containing phenylpyrimidinone hydrochloride, pharmaceutical preparation containing same, and preparation method and application of pharmaceutical composition Download PDFInfo
- Publication number
- CN114344306A CN114344306A CN202210079753.0A CN202210079753A CN114344306A CN 114344306 A CN114344306 A CN 114344306A CN 202210079753 A CN202210079753 A CN 202210079753A CN 114344306 A CN114344306 A CN 114344306A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical composition
- compound
- formula
- phenylpyrimidinone
- filler
- 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
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 49
- -1 phenylpyrimidinone hydrochloride Chemical compound 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title abstract description 29
- 239000000825 pharmaceutical preparation Substances 0.000 title abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 57
- 238000002156 mixing Methods 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 36
- 239000000463 material Substances 0.000 claims abstract description 24
- 239000003814 drug Substances 0.000 claims abstract description 18
- 239000003937 drug carrier Substances 0.000 claims abstract description 15
- 229940079593 drug Drugs 0.000 claims abstract description 11
- 239000003826 tablet Substances 0.000 claims description 36
- 239000002775 capsule Substances 0.000 claims description 32
- 239000000945 filler Substances 0.000 claims description 30
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 30
- 239000000314 lubricant Substances 0.000 claims description 26
- 239000007884 disintegrant Substances 0.000 claims description 24
- 239000011230 binding agent Substances 0.000 claims description 19
- 239000000843 powder Substances 0.000 claims description 18
- 239000002245 particle Substances 0.000 claims description 17
- 238000011049 filling Methods 0.000 claims description 16
- 239000000853 adhesive Substances 0.000 claims description 15
- 230000001070 adhesive effect Effects 0.000 claims description 15
- 235000019359 magnesium stearate Nutrition 0.000 claims description 15
- 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 claims description 13
- 239000008187 granular material Substances 0.000 claims description 13
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 12
- 229920002472 Starch Polymers 0.000 claims description 12
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 12
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 12
- 239000008107 starch Substances 0.000 claims description 12
- 235000019698 starch Nutrition 0.000 claims description 12
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 11
- 239000008101 lactose Substances 0.000 claims description 11
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 11
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 11
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- 201000001881 impotence Diseases 0.000 claims description 10
- 208000010228 Erectile Dysfunction Diseases 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 239000011812 mixed powder Substances 0.000 claims description 9
- 239000011734 sodium Substances 0.000 claims description 9
- 229910052708 sodium Inorganic materials 0.000 claims description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 8
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 8
- 229940069328 povidone Drugs 0.000 claims description 8
- 238000010298 pulverizing process Methods 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 238000005469 granulation Methods 0.000 claims description 5
- 230000003179 granulation Effects 0.000 claims description 5
- 238000007873 sieving Methods 0.000 claims description 5
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 4
- 229960000913 crospovidone Drugs 0.000 claims description 4
- 208000035475 disorder Diseases 0.000 claims description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 4
- 206010002388 Angina unstable Diseases 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 3
- 206010071445 Bladder outlet obstruction Diseases 0.000 claims description 3
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 3
- 229920002261 Corn starch Polymers 0.000 claims description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 3
- 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 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 3
- 208000005171 Dysmenorrhea Diseases 0.000 claims description 3
- 206010013935 Dysmenorrhoea Diseases 0.000 claims description 3
- 102000004190 Enzymes Human genes 0.000 claims description 3
- 108090000790 Enzymes Proteins 0.000 claims description 3
- 206010057671 Female sexual dysfunction Diseases 0.000 claims description 3
- 208000010412 Glaucoma Diseases 0.000 claims description 3
- 206010019280 Heart failures Diseases 0.000 claims description 3
- 206010020772 Hypertension Diseases 0.000 claims description 3
- 206010021639 Incontinence Diseases 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 208000018262 Peripheral vascular disease Diseases 0.000 claims description 3
- 208000006399 Premature Obstetric Labor Diseases 0.000 claims description 3
- 206010036600 Premature labour Diseases 0.000 claims description 3
- 201000001068 Prinzmetal angina Diseases 0.000 claims description 3
- 208000004403 Prostatic Hyperplasia Diseases 0.000 claims description 3
- 208000003782 Raynaud disease Diseases 0.000 claims description 3
- 208000012322 Raynaud phenomenon Diseases 0.000 claims description 3
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 3
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 208000006011 Stroke Diseases 0.000 claims description 3
- 208000007814 Unstable Angina Diseases 0.000 claims description 3
- 208000003800 Urinary Bladder Neck Obstruction Diseases 0.000 claims description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- 201000010105 allergic rhinitis Diseases 0.000 claims description 3
- 206010006451 bronchitis Diseases 0.000 claims description 3
- 208000023819 chronic asthma Diseases 0.000 claims description 3
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 3
- 239000008120 corn starch Substances 0.000 claims description 3
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 3
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 3
- 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 claims description 3
- 208000027866 inflammatory disease Diseases 0.000 claims description 3
- 201000004332 intermediate coronary syndrome Diseases 0.000 claims description 3
- 201000006370 kidney failure Diseases 0.000 claims description 3
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 239000006187 pill Substances 0.000 claims description 3
- 208000026440 premature labor Diseases 0.000 claims description 3
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 3
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims description 3
- 235000010356 sorbitol Nutrition 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 2
- 101100189582 Dictyostelium discoideum pdeD gene Proteins 0.000 claims 2
- 101150098694 PDE5A gene Proteins 0.000 claims 2
- 102100029175 cGMP-specific 3',5'-cyclic phosphodiesterase Human genes 0.000 claims 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 19
- 238000005550 wet granulation Methods 0.000 abstract description 16
- 238000004090 dissolution Methods 0.000 abstract description 13
- 238000004134 energy conservation Methods 0.000 abstract description 4
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 230000000670 limiting effect Effects 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 abstract description 2
- 238000012216 screening Methods 0.000 abstract description 2
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 21
- 239000011248 coating agent Substances 0.000 description 17
- 238000000576 coating method Methods 0.000 description 17
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 10
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 229940032147 starch Drugs 0.000 description 10
- 238000005303 weighing Methods 0.000 description 10
- 229960003310 sildenafil Drugs 0.000 description 9
- 238000011156 evaluation Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000000634 powder X-ray diffraction Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000007916 tablet composition Substances 0.000 description 6
- WOXKDUGGOYFFRN-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 WOXKDUGGOYFFRN-IIBYNOLFSA-N 0.000 description 6
- 229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 description 5
- SECKRCOLJRRGGV-UHFFFAOYSA-N Vardenafil Chemical compound CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 SECKRCOLJRRGGV-UHFFFAOYSA-N 0.000 description 5
- WEAJZXNPAWBCOA-INIZCTEOSA-N avanafil Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2[C@@H](CCC2)CO)=NC=C1C(=O)NCC1=NC=CC=N1 WEAJZXNPAWBCOA-INIZCTEOSA-N 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 238000007908 dry granulation Methods 0.000 description 5
- 229960000835 tadalafil Drugs 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 229960000307 avanafil Drugs 0.000 description 4
- 238000007907 direct compression Methods 0.000 description 4
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- 229960002381 vardenafil Drugs 0.000 description 4
- 230000004580 weight loss Effects 0.000 description 4
- LDORHCBMWSQLIU-UHFFFAOYSA-N 6-phenyl-1h-pyrimidin-2-one Chemical compound N1C(=O)N=CC=C1C1=CC=CC=C1 LDORHCBMWSQLIU-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000007888 film coating Substances 0.000 description 3
- 238000009501 film coating Methods 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 101100351286 Dictyostelium discoideum pdeE gene Proteins 0.000 description 2
- 101001117089 Drosophila melanogaster Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1 Proteins 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000005429 filling process Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 238000005461 lubrication Methods 0.000 description 2
- 229940057948 magnesium stearate Drugs 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 101150037969 pde-6 gene Proteins 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 238000004080 punching Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000010008 shearing Methods 0.000 description 2
- 235000015424 sodium Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 229940033134 talc Drugs 0.000 description 2
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- 101001072031 Drosophila melanogaster Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11 Proteins 0.000 description 1
- 241000893536 Epimedium Species 0.000 description 1
- 206010016825 Flushing Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108010044467 Isoenzymes Proteins 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- OXNGBNVLPXLUPV-UHFFFAOYSA-N N-[3-(4,5-diethyl-6-oxo-1H-pyrimidin-2-yl)-4-propoxyphenyl]-2-(4-methylpiperazin-1-yl)acetamide hydrochloride Chemical compound CCCOC1=C(C=C(C=C1)NC(=O)CN2CCN(CC2)C)C3=NC(=C(C(=O)N3)CC)CC.Cl OXNGBNVLPXLUPV-UHFFFAOYSA-N 0.000 description 1
- 229920003081 Povidone K 30 Polymers 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 201000001880 Sexual dysfunction Diseases 0.000 description 1
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 description 1
- 102000011016 Type 5 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 1
- 108010037581 Type 5 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 1
- 206010047571 Visual impairment Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940117229 cialis Drugs 0.000 description 1
- 238000003759 clinical diagnosis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 235000013365 dairy product Nutrition 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 210000003298 dental enamel Anatomy 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 235000018905 epimedium Nutrition 0.000 description 1
- 230000009986 erectile function Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 150000002212 flavone derivatives Chemical class 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 229940097443 levitra Drugs 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 208000015001 muscle soreness Diseases 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000018052 penile erection Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000007779 soft material Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229940046921 stendra Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229940094720 viagra Drugs 0.000 description 1
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a pharmaceutical composition containing phenyl pyrimidone hydrochloride, a pharmaceutical preparation containing the same, and a preparation method and application of the pharmaceutical composition. Specifically, the pharmaceutical compositions of the present invention comprise a compound of formula I-A, and a pharmaceutically acceptable carrier. The problems of mixing uniformity, content uniformity and slow dissolution are solved by limiting the granularity of the compound shown in the formula I-A, screening the composition and the dosage of auxiliary materials and researching the preparation process. The pharmaceutical composition or the pharmaceutical preparation has good content uniformity, good stability and rapid disintegration, can realize rapid dissolution, can be prepared by adopting two processes of direct mixing or wet granulation, preferentially adopts the direct mixing process, and has the characteristics of simple prescription process, low cost, energy conservation, environmental protection, easy industrial application and the like.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a pharmaceutical composition containing phenyl pyrimidone hydrochloride, a pharmaceutical preparation containing the same, a preparation method of the pharmaceutical composition, and application of the pharmaceutical composition or the pharmaceutical preparation in the aspect of medicines.
Background
Erectile Dysfunction (ED), commonly known as "impotence," refers to the inability of a man to achieve or maintain penile erection of sufficient rigidity to complete a satisfactory sexual life, with a clinical diagnosis of ED over 3 months. Epidemiological data (J android, 2011,32: 496).
In the drug treatment of ED, a Phosphodiesterase 5(PDE5) inhibitor is convenient, safe and effective to use, is easily accepted by most patients, and is the first choice drug in clinic at present. Currently marketed oral PDE5 inhibitors for the treatment of erectile dysfunction are: sildenafil (Sildenafil, Viagra), Vardenafil (Vardenafil, Levitra), Tadalafil (Tadalafil, Cialis) and Avanafil (Avanafil, Stendra). Sildenafil, developed by the U.S. pfeir company, was approved by the U.S. FDA for marketing in 1998, was the first oral drug approved by the U.S. FDA for treating ED. Then in 2003, Vardenafil was released by Bayer in conjunction with Kurarin Schker and tadalafil was released by Shilekusan. In 2012, the FDA approved avanafil for marketing.
Since phosphodiesterases have at least 11 enzyme lines and more subtypes, highly selective inhibitors of PDE5 are key to the development of therapeutics for sexual dysfunction. Of the four PDE5 inhibitors which are currently on the market, sildenafil and vardenafil have poor selectivity on PDE1 and PDE6, cause side effects such as facial flushing, visual disturbance and the like, have potential cardiovascular risks, and are short in half-life period and not suitable for long-term administration; the tadalafil has longer half-life and can be taken once a day, but the tadalafil has poor selectivity on PDE11, and the side effects of back pain and muscle soreness influence the medication compliance of patients; avanafil has low clinical adverse reactions due to high selectivity, but has short half-life and is not suitable for long-term administration. There remains an unmet clinical need for PDE5 inhibitors, and highly selective, long half-life PDE5 inhibitors are the direction of development of a new generation of PDE inhibitors.
Chinese granted patent publication No. CN102216279B discloses a phenyl pyrimidinone compound and its pharmaceutically acceptable salts, a compound having higher phosphodiesterase 5(PDE5) inhibitory activity. The compound takes natural product epimedium flavone as leadThe structure takes analytical data of computational chemistry as reference, and carries out fine 'structure fine tuning' design and synthesis work through structure modification and splicing synthesis technology, and finally obtains a candidate compound with better druggability comprehensive evaluation than sildenafil. The activity (IC) of the phenylpyrimidinone compound can be found from studies on preclinical toxicological, pharmacodynamic and pharmacokinetic properties and the like500.62nM) and sildenafil (IC)504.31nM), and compared with other isozymes, the selectivity (including PDE1 and PDE6) is significantly improved compared with sildenafil, and compared with sildenafil, the novel compound has the advantages of high activity, high selectivity, low toxicity, definite drug effect, simple structure, easy synthesis and the like.
Based on animal experimental data of preclinical oral administration, the compound can be developed into an oral solid preparation, the administration mode is oral gastrointestinal administration, and the intracellular cGMP level is improved by inhibiting the activity of PDE5 enzyme, so that the erectile function is enhanced.
However, in the phenyl pyrimidone compound preparation, since the phenyl pyrimidone compound accounts for a relatively small amount, the problem of mixing uniformity is easily caused in the preparation process, and the problem of slow dissolution of the finished preparation is easily caused. Therefore, the invention aims to solve the technical problems of preparing the phenyl pyrimidone-containing pharmaceutical composition or pharmaceutical preparation with good content uniformity, good stability, rapid disintegration, capability of realizing rapid dissolution, simple prescription process, low cost, energy conservation and environmental protection.
Disclosure of Invention
Problems to be solved by the invention
In order to solve the problems, the invention provides a pharmaceutical composition containing phenylpyrimidinone hydrochloride, a pharmaceutical preparation containing the same, and a preparation method and application of the pharmaceutical composition.
Means for solving the problems
In a first aspect, the present invention provides a pharmaceutical composition comprising a phenylpyrimidinone hydrochloride, comprising a compound of formula I-A, and a pharmaceutically acceptable carrier.
Wherein the particle size D of the compound of formula I-A90≤30μm。
Preferably, the particle size D of the compound of formula I-A90≤20μm。
Preferably, the pharmaceutically acceptable carrier includes a filler, a disintegrant, a binder, and a lubricant.
More preferably, the pharmaceutically acceptable carrier consists of a filler, a disintegrant, a binder and a lubricant.
Preferably, the pharmaceutical composition comprises the following components in percentage by weight: 1-20% of a compound of formula I-A, 35-90% of a filler, 1-20% of a disintegrating agent, 1-20% of an adhesive and 0.1-5% of a lubricant.
More preferably, the pharmaceutical composition comprises the following components in percentage by weight: 1-10% of a compound of formula I-A, 72-90% of a filler, 1-8% of a disintegrating agent, 1-8% of an adhesive and 0.5-2% of a lubricant.
Preferably, the filler is at least one of lactose, corn starch, mannitol, sorbitol and microcrystalline cellulose, the disintegrant is at least one of low-substituted hydroxypropyl cellulose, croscarmellose sodium, carboxymethyl starch sodium and crospovidone, the binder is at least one of hydroxypropyl cellulose, hydroxypropyl methylcellulose and povidone, and the lubricant is at least one of magnesium stearate, sodium stearyl fumarate, talc and colloidal silicon dioxide.
More preferably, the filler is lactose and microcrystalline cellulose, the disintegrant is carboxymethyl starch sodium, the binder is povidone, and the lubricant is magnesium stearate.
In a second aspect, the present invention provides a method for preparing the above pharmaceutical composition, which comprises the following steps: mixing a compound of formula I-A and a pharmaceutically acceptable carrier.
In a third aspect, the invention provides a pharmaceutical preparation, which is prepared from the pharmaceutical composition.
Preferably, the pharmaceutical preparation is a tablet, a capsule, a granule, a pill, a powder or a dry suspension.
More preferably, the pharmaceutical formulation is a tablet or capsule.
In a fourth aspect, the present invention provides a method for preparing the above pharmaceutical preparation, wherein the method can be selected from direct mixing, wet granulation or dry granulation, and preferably from direct mixing.
The preparation method comprises the following steps:
(1) pulverizing the compound of formula I-A to a target particle size, sieving the filler, disintegrant, binder and lubricant;
(2) uniformly mixing the compound of formula I-A crushed in the step (1) and the sieved filler, disintegrant and adhesive to obtain a mixed material; or
Uniformly mixing the compound of formula I-A crushed in the step (1) with the sieved filler and disintegrant, and adding the sieved adhesive solution in the step (1) for granulation to obtain drug-containing granules;
(3) adding the lubricant sieved in the step (1) into the mixed material or the medicine-containing granules in the step (2), and uniformly mixing to obtain total mixed powder;
(4) and (4) tabletting or filling the total mixed powder in the step (3) into capsules.
Preferably, the filler, disintegrant, binder and lubricant in step (1) are sieved through an 80 mesh sieve.
Preferably, step (4) further comprises a step of coating after tabletting.
In a fifth aspect, the invention provides the use of a pharmaceutical composition as described above or a pharmaceutical formulation as described above in the manufacture of a medicament for the treatment and/or prevention of a disease and/or condition associated with the PDE5 enzyme.
Preferably, the disease and/or condition associated with the PDE5 enzyme comprises: erectile dysfunction, pulmonary hypertension, female sexual dysfunction, premature labor, dysmenorrhea, benign prostatic hyperplasia, bladder outlet obstruction, incontinence, unstable and variant angina, hypertension, congestive heart failure, renal failure, atherosclerosis, stroke, peripheral vascular disease, raynaud's disease, inflammatory diseases, bronchitis, chronic asthma, allergic rhinitis, glaucoma, and disorders of bowel movement.
ADVANTAGEOUS EFFECTS OF INVENTION
The invention provides a pharmaceutical composition containing phenylpyrimidinone hydrochloride, a pharmaceutical preparation containing the same, a preparation method and application of the pharmaceutical composition, wherein the composition specifically comprises a compound shown in a formula I-A and a pharmaceutically acceptable carrier. The problems of mixing uniformity, content uniformity and slow dissolution are solved by limiting the granularity of the compound shown in the formula I-A, combining auxiliary materials and screening the dosage and carrying out a large number of experimental researches on the preparation process. The pharmaceutical composition or the pharmaceutical preparation has good content uniformity, good stability and rapid disintegration, can realize rapid dissolution, can be prepared by adopting two processes of direct mixing or wet granulation, preferentially adopts the direct mixing process, and has the characteristics of simple prescription process, low cost, energy conservation, environmental protection, easy industrial application and the like.
Drawings
Figure 1 shows the XRPD pattern of the compound of formula I-a (not milled).
Figure 2 shows the XRPD pattern of the compound of formula I-a (crush treatment).
Figure 3 shows the XRPD pattern of the compound of formula I-a (simulated wet granulation).
Detailed Description
[ definition of terms ]
Phenylpyrimidinone hydrochloride
The 'phenyl pyrimidone compound' is a compound with a phenyl pyrimidone structure, and a Chinese granted patent with the publication number of CN102216279B discloses a phenyl pyrimidone compound and pharmaceutically acceptable salts thereof, which have higher phosphodiesterase (PDE5) inhibition activity and better comprehensive pharmaceutical evaluation than sildenafil. "phenylpyrimidinone hydrochloride" refers to the hydrochloride salt of a phenylpyrimidinone compound.
Compounds of formula I-A
The compound of the formula I-A is hydrochloride of a phenyl pyrimidone compound, and has the following structure and the chemical name: 5, 6-diethyl-2- [ 2-n-propoxy-5- (2- (4-methylpiperazin-1-yl) acetamido) phenyl ] pyrimidin-4 (3H) -one hydrochloride.
Pharmaceutically acceptable carriers
By "pharmaceutically acceptable carrier" is meant a pharmaceutical excipient that is compatible with the pharmaceutically active ingredient and not deleterious to the subject, including, but not limited to, fillers, binders, disintegrants, lubricants, wetting agents, thickening agents, glidants, flavoring agents, olfactory agents, preservatives, antioxidants, pH adjusters, solvents, cosolvents, surfactants, and the like.
[ pharmaceutical composition ]
The invention provides a pharmaceutical composition containing phenylpyrimidinone hydrochloride, which comprises a compound shown as a formula I-A and a pharmaceutically acceptable carrier.
In one embodiment, the particle size D of the compound of formula I-A90≤30μm。
In a preferred embodiment, the particle size D of the compound of formula I-A90≤20μm。
In one embodiment, the pharmaceutically acceptable carrier includes a filler, a disintegrant, a binder, and a lubricant.
In a preferred embodiment, the pharmaceutically acceptable carrier consists of a filler, a disintegrant, a binder and a lubricant.
In one embodiment, the pharmaceutical composition comprises the following components in weight percent: 1-20% of a compound of formula I-A, 35-90% of a filler, 1-20% of a disintegrating agent, 1-20% of an adhesive and 0.1-5% of a lubricant.
In a preferred embodiment, the pharmaceutical composition comprises the following components in weight percent: 1-10% of a compound of formula I-A, 72-90% of a filler, 1-8% of a disintegrating agent, 1-8% of an adhesive and 0.5-2% of a lubricant.
In one embodiment, the filler is at least one of lactose, corn starch, mannitol, sorbitol, and microcrystalline cellulose, the disintegrant is at least one of low-substituted hydroxypropyl cellulose, croscarmellose sodium, carboxymethyl starch sodium, and crospovidone, the binder is at least one of hydroxypropyl cellulose, hydroxypropyl methylcellulose, and povidone, and the lubricant is at least one of magnesium stearate, sodium stearyl fumarate, talc, and colloidal silicon dioxide.
In a preferred embodiment, the fillers are lactose and microcrystalline cellulose, the disintegrant is sodium starch glycolate, the binder is povidone, and the lubricant is magnesium stearate.
[ Process for producing pharmaceutical composition ]
The invention provides a preparation method of the pharmaceutical composition, which comprises the following steps: mixing a compound of formula I-A and a pharmaceutically acceptable carrier.
[ pharmaceutical preparations ]
The invention provides a pharmaceutical preparation, which is prepared from the pharmaceutical composition.
In one embodiment, the pharmaceutical formulation is a tablet, capsule, granule, pill, powder, or dry suspension.
In a preferred embodiment, the pharmaceutical formulation is a tablet or capsule.
[ Process for producing pharmaceutical preparation ]
The invention provides a preparation method of the pharmaceutical preparation, which can select a preparation method of direct mixing, wet granulation or dry granulation, and preferably a preparation method of direct mixing.
The preparation method comprises the following steps:
(1) pulverizing the compound of formula I-A to a target particle size, sieving the filler, disintegrant, binder and lubricant;
(2) uniformly mixing the compound of formula I-A crushed in the step (1) and the sieved filler, disintegrant and adhesive to obtain a mixed material; or
Uniformly mixing the compound of formula I-A crushed in the step (1) with the sieved filler and disintegrant, and adding the sieved adhesive solution in the step (1) for granulation to obtain drug-containing granules;
(3) adding the lubricant sieved in the step (1) into the mixed material or the medicine-containing granules in the step (2), and uniformly mixing to obtain total mixed powder;
(4) and (4) tabletting or filling the total mixed powder in the step (3) into capsules.
In one embodiment, the filler, disintegrant, binder and lubricant in step (1) are sieved through an 80 mesh sieve.
In one embodiment, step (4) further comprises the step of coating after tableting.
[ medical use ]
The invention provides the application of the pharmaceutical composition or the pharmaceutical preparation in preparing medicines for treating and/or preventing diseases and/or symptoms related to PDE5 enzyme.
In one embodiment, the disease and/or condition associated with the PDE5 enzyme comprises: erectile dysfunction, pulmonary hypertension, female sexual dysfunction, premature labor, dysmenorrhea, benign prostatic hyperplasia, bladder outlet obstruction, incontinence, unstable and variant angina, hypertension, congestive heart failure, renal failure, atherosclerosis, stroke, peripheral vascular disease, raynaud's disease, inflammatory diseases, bronchitis, chronic asthma, allergic rhinitis, glaucoma, and disorders of bowel movement.
The present invention will be described in further detail below with reference to examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples. Various substitutions and alterations according to the general knowledge and conventional practice in the art are intended to be included within the scope of the present invention without departing from the technical spirit of the present invention as described above.
The method for detecting evaluation indexes such as disintegration time limit, friability, mixing uniformity, content uniformity, dissolution curve, appearance, powder flowability and the like in the embodiment or specific example of the present invention is as follows:
disintegration time limit: by adopting a method for checking the disintegration time limit of 0921 in the '2020 edition of Chinese pharmacopoeia', the tablet can be completely disintegrated in 900ml of water at 37 +/-1 ℃ within 30 minutes and passes through a screen, and if a small amount of light matter floats upwards or is adhered to a stainless steel pipe or the screen, but no hard core exists, the tablet can be taken as meeting the regulation theory. And (4) repeatedly measuring 6 pieces, wherein all the pieces meet the requirements, and if one piece does not meet the requirements, taking another 6 pieces for retesting, wherein all the pieces meet the requirements.
Friability: the method comprises the steps of adopting a tablet friability checking method of 0923 in 'Chinese pharmacopoeia' 2020 edition, using a tablet friability tester, taking a plurality of tablets to enable the total weight of the tablets to be about 6.5g, blowing off powder falling off from the tablets by using a blower, precisely weighing the tablets, placing the tablets in a cylinder, rotating the cylinders for 100 times, taking out the tablets, removing the powder by the same method, precisely weighing the tablets until the weight loss is less than 1%, and not checking the broken, cracked and crushed tablets. If the weight loss exceeds 1%, the weight loss should be measured 2 times, and the average weight loss of 3 times should not exceed 1%, and no fracture, crack or crushed piece should be detected.
Mixing uniformity: the content detection method is adopted, 10 mixed medicinal powders at different positions are taken, the content is detected, and the RSD value is calculated according to the content result, wherein the RSD value is generally considered to be less than 5 percent, so that the requirement of mixing uniformity is met.
Content uniformity: a content detection method is adopted, the content of a single measurement unit material amount (no less than 10 sampling points) is respectively detected, an A +2.2S value is calculated according to a content result, generally, the A +2.2 is considered to be less than 15, and the requirement of content uniformity is met.
Dissolution: the second method of 0931 dissolution and release determination method is adopted in 'Chinese pharmacopoeia' 2020 edition, and 0.1mol/L hydrochloric acid solution is adopted as dissolution medium, and the sampling time is as follows: 5. 10, 15, 30, 45min, medium volume 900ml, rotation speed: dissolution was measured at 50rpm, with the limits required: the amount eluted in 45 minutes should be not less than 80% of the indicated amount.
Plain sheet appearance: by adopting the contents of the general rule of 'Chinese pharmacopoeia' 2020 edition, 0101 tablet preparation, the plain tablet has complete and smooth appearance, uniform color, no sticking and uncovering, and proper hardness and wear resistance, so that the plain tablet is prevented from being worn and broken in the packaging and transportation processes.
Powder flowability: the common angle of repose indicates that the angle of repose is the maximum angle formed by the free slope of the powder accumulation layer and the horizontal plane, the smaller the angle of repose is, the smaller the friction force is, the better the fluidity is when the angle of repose is less than 30 degrees, and the fluidity requirement in the production process can be met when the angle of repose is less than 40 degrees. And >40 deg., the flowability requirement in the production process is generally considered to be not satisfied.
In order to solve the technical problems of small-dose medicine mixing uniformity, content uniformity and the like, the invention screens the use amount of auxiliary materials such as a filling agent, a disintegrating agent, an adhesive and the like and researches a large number of preparation process experiments, and inspects the indexes of the mixing uniformity, the content uniformity, the disintegration time limit, the friability, the powder flowability, the plain tablet appearance and the like of the pharmaceutical composition containing the phenyl pyrimidone hydrochloride.
The following examples are not specifically illustrated, and all starting materials and reagents are commercially available or prepared by conventional methods in the art. Wherein the compounds of formula I-A are purchased from Shandong Tei enamel pharmaceutical Co., Ltd, lactose (trade designations: G200, F100) is purchased from Deltakutazeugo Dairy, Germany, microcrystalline cellulose (trade designations: PH101, PH102) is purchased from Asahi Kasei-Kasei corporation, carboxymethyl starch sodium (trade designation: ZW-SSG-D) is purchased from Huzhou Yongyasu pharmaceutical Co., Ltd, povidone (trade designation: polyvinylpyrrolidone, trade designation: K30) is purchased from U.S. Pasteur Co., Ltd, starch, magnesium stearate (trade designation: SH-YM-M) is purchased from Anhui Shanhe pharmaceutical excipients Co., Ltd, film coating agents (trade designation: Opadry YS-1-7027CN) are purchased from Shanghai Kalerkang coating technology Co., Ltd, and gelatin hollow capsule shells (trade designations: 1#, 2#) are purchased from Suzhou capsule Co., Ltd.
Example 1: tablet formulation (direct compression)
The preparation process comprises the following steps:
(1) material pretreatment: pulverizing the compound of formula I-A, and determining the particle size D9018.8 μm; the auxiliary materials are sieved by a 80-mesh sieve for standby.
(2) Weighing: weighing the compound of formula I-A, lactose, microcrystalline cellulose, carboxymethyl starch sodium, polyvidone and magnesium stearate according to the prescription amount.
(3) Mixing: the components other than magnesium stearate were added to the hopper mixer at a rotation speed of 10rpm/min and mixed for 10 minutes.
(4) Lubrication: adding magnesium stearate, setting the rotating speed to be 10rpm/min, and mixing for 5 minutes to obtain total mixed powder; a total of 10 spots were sampled at different locations of the mixer to determine the uniformity of mixing. The particle content was measured and the tablet weight was calculated.
(5) Tabletting: tabletting by adopting a rotary tablet press, and tabletting a mould: the 6.5mm circular shallow concave punching die is controlled in the hardness range of 40-80N, the weight of the tablet is about 125mg, the weight difference limit is +/-5.0%, and sampling is carried out to determine the friability, the content and the like.
(6) Coating: adopting a film coating premix (Opadry YS-1-7027CN), weighing coating powder with a quantity of 4.0% of the single-pot quantity of the tablet core, adding the coating powder into purified water, stirring and dispersing uniformly to prepare a 15% (w/w) coating solution; and (3) placing the tablet core into a coating pot, setting the air inlet temperature to be 55-65 ℃, controlling the material temperature to be 40-60 ℃, setting the rotating speed of the pot body to be 1-10 rpm/min, and performing coating operation according to a coating program to control the coating weight to be increased by 1-3%.
Example 2: tablet formulation (Wet granulation)
The preparation process comprises the following steps:
(1) material pretreatment: pulverizing the compound of formula I-A, and determining the particle size D9018.8 μm; the auxiliary materials are sieved by a 80-mesh sieve for standby.
(2) Weighing: weighing the compound of formula I-A, lactose, microcrystalline cellulose, carboxymethyl starch sodium, polyvidone and magnesium stearate according to the prescription amount.
(3) Preparing a binder solution: the povidone K30 with the prescription amount is added into the 50 percent ethanol solution and stirred continuously to prepare clear 5 percent (w/w) povidone ethanol solution for standby.
(3) Premixing: adding other components except magnesium stearate into high speed wet granulating machine, stirring at 180rpm/min, and mixing for 10 min.
(4) And (3) granulating: setting the stirring speed of 180rpm/min and the shearing speed of 1200rpm/min, adding the adhesive solution for granulation, controlling the slurry adding time within 5min, setting the stirring speed of 180rpm/min and the shearing speed of 2000pm/min after the slurry adding is finished, and stirring for 5 min.
(5) Wet granulation: wet-granulating the granulated material by a swinging granulator (20-mesh screen).
(6) And (3) drying: adding the wet material into a boiling dryer, controlling the air inlet temperature at 60 ℃, and drying until the moisture is below 3.0% (measured by a halogen rapid moisture meter, 105 ℃/5 min).
(7) Dry granulation: and (3) carrying out dry granulation on the dried material by a crushing and granulating machine (granulation rotating speed is 1000rpm/min, and a V-shaped screen is 2.0 mm).
(8) Lubrication: adding magnesium stearate, setting the rotating speed to be 10rpm/min, and mixing for 5 minutes to obtain total mixed powder; a total of 10 spots were sampled at different locations of the mixer to determine the uniformity of mixing. The particle content was measured and the tablet weight was calculated.
(9) Tabletting: tabletting by adopting a rotary tablet press, and tabletting a mould: and (3) carrying out 6.5mm circular shallow concave punching, controlling the hardness range to be 40-80N, controlling the weight of the tablet to be about 125mg, and measuring the friability, the content and the like by sampling, wherein the weight difference limit is +/-5.0%.
(10) Coating: adopting a film coating premix (Opadry YS-1-7027CN), weighing coating powder with a quantity of 4.0% of the single-pot quantity of the tablet core, adding the coating powder into purified water, stirring and dispersing uniformly to prepare a 15% (w/w) coating solution; and (3) placing the tablet core into a coating pot, setting the air inlet temperature to be 55-65 ℃, controlling the material temperature to be 40-60 ℃, setting the rotating speed of the pot body to be 1-10 rpm/min, and performing coating operation according to a coating program to control the coating weight to be increased by 1-3%.
Example 3: tablet formulation (direct compression)
The preparation process is the same as in example 1.
Example 4: capsule prescription (direct mixing)
The process before capsule filling is the same as that of example 1, and the capsule filling steps are as follows: filling the capsule with No. 2 capsule by using a capsule filling plate, wherein the average filling weight is about 125 mg; and monitoring the product characters and weight difference in the filling process. The capsule properties are as follows: removing capsule shell to obtain white or quasi-white powder; limit of weight difference: 5.0 percent.
Example 5: capsule prescription (Wet granulation)
The process before capsule filling was the same as example 2, capsule filling: filling the capsule with No. 2 capsule by using a capsule filling plate, wherein the average filling weight is about 125 mg; and monitoring the product characters and weight difference in the filling process. The capsule properties are as follows: removing capsule shell to obtain white or quasi-white powder; limit of weight difference: 5.0 percent.
Example 6: capsule prescription (Wet granulation)
The prescription and the process design of the embodiment refer to the description of the granted patent (granted publication No. CN102216279B) at the 973-977 paragraph "the embodiment 222 capsule", and the preparation process is as follows: pulverizing the compound of formula I-A, and determining the particle size D9018.8 μm; sieving compound containing formula I-A and adjuvants such as starch, lactose and microcrystalline cellulose with 80 mesh sieve, weighing according to prescription, using 10% polyvinylpyrrolidone ethanol solution as binder, making into appropriate granule with 16 mesh sieve, drying at 65 deg.C, grading with 14 mesh sieve, adding magnesium stearate, and mixingAnd (3) homogenizing, measuring the content of the particles, calculating the filling amount, and filling into capsules (the average filling weight is 198mg) by using No. 1 capsules.
Example 7: tablet formulation (Wet granulation)
The prescription and the process design of the embodiment refer to the specification of the granted patent (granted publication No: CN102216279B) No. 978-980 paragraph "tablet of the embodiment 223 (wet granulation method)", and the preparation process is as follows: pulverizing the compound of formula I-A, and determining the particle size D9018.8 μm; sieving a compound containing the formula I-A and auxiliary materials of lactose, microcrystalline cellulose and sodium carboxymethyl starch by a sieve of 80 meshes, weighing according to the prescription amount, preparing a soft material by using 8% starch slurry, granulating by using a sieve of 16 meshes, drying, finishing granules, adding magnesium stearate, uniformly mixing, measuring the content of the granules, calculating the weight of the tablets, and tabletting (8.0 mm circular shallow concave punch die is adopted for tabletting, the hardness interval is controlled to be 60-100N, and the average value of the weight of the tablets is about 200 mg).
Example 8: tablet formulation (direct compression)
The preparation process is similar to example 1 except that the disintegrant and binder of example 8 are crospovidone and hydroxypropylcellulose.
Comparative example 1: tablet formulation (direct compression)
The preparation process is the same as example 1, except that: comparative example 1 Using the Compound of formula I-A without comminution treatment (found value: D)9088 μm) was prepared.
Comparative example 2: capsule prescription (Wet granulation)
The preparation process is the same as example 6, except that: comparative example 2 Using the Compound of formula I-A without pulverization treatment (found value: D)9088 μm) was prepared.
And (3) crystal form detection:
the crystal forms of the compound of formula I-A (not crushed), the compound of formula I-A (crushed) and the compound of formula I-A (simulated wet granulation, wetting by adding a small amount of solvent and drying) are determined by an X-ray powder diffraction method, and the XRPD patterns are respectively shown in figure 1, figure 2 and figure 3. The XRPD crystal form pattern shows that the compound of the formula I-A has stable crystal form and does not generate crystal form transformation in the process of crushing or simulating wet granulation, and the compound is supposed to have ideal stability in the subsequent preparation process.
Evaluation results table 1:
evaluation results table 2:
evaluation results table 3:
note: in the above 3 evaluation result tables, CR means a cumulative elution rate (cumulative release rate).
And (4) analyzing results:
the specific auxiliary material combination is adopted in the examples 1-8, the prepared tablet or capsule has good disintegration effect, and complete disintegration can be realized within 30 min. The auxiliary material combination of the examples 1 to 5 has better disintegration effect compared with the examples 6 to 8, complete disintegration can be realized within 10min, the examples 1 to 5 can realize rapid dissolution, and the examples 6 to 8 have slower dissolution.
The raw materials used in examples 1-8 were all mechanically crushed to control the particle size D of the material90Less than or equal to 30 mu m (measured value is D)9018.8 mu m), the prepared total mixed powder of the materials has better mixing uniformity and finished product content uniformity; comparative examples 1-2 use an unpulverized crude drug (found D)9088 μm) is directly mixed or wet granulated, and the flowability, mixing uniformity and content uniformity of the finished product of the material powder are relatively poor.
The flowability and compressibility of the intermediate powder in the two processes of direct mixing and wet granulation in examples 1 to 5 are all in accordance with requirements, the disintegration effect and dissolution behavior of each process are almost the same, the difference is small, the weight difference/loading difference, the content and the content uniformity are all in accordance with requirements, and the process steps are simple, special production conditions and production equipment are not needed, the cost is low, and the method is suitable for industrial production. The two processes are preferably direct mixing processes, so that the steps of wet granulation, drying, dry granulation and the like are reduced, the operation is simpler and more convenient, the environment protection, energy conservation and emission reduction are facilitated, and the method is more suitable for industrial production.
Claims (9)
1. A pharmaceutical composition comprising a phenylpyrimidinone hydrochloride comprising a compound of formula I-a, and a pharmaceutically acceptable carrier;
wherein the particle size D of the compound of formula I-A90Less than or equal to 30 μm, preferably the particle size D90≤20μm。
2. The pharmaceutical composition comprising a phenylpyrimidinone hydrochloride of claim 1, wherein:
the pharmaceutically acceptable carrier includes a filler, a disintegrant, a binder, and a lubricant.
3. The pharmaceutical composition comprising a phenylpyrimidinone hydrochloride according to claim 2, wherein:
the pharmaceutical composition comprises the following components in percentage by weight: 1-20% of a compound of formula I-A, 35-90% of a filler, 1-20% of a disintegrating agent, 1-20% of an adhesive and 0.1-5% of a lubricant;
preferably, the pharmaceutical composition comprises the following components in percentage by weight: 1-10% of a compound of formula I-A, 72-90% of a filler, 1-8% of a disintegrating agent, 1-8% of an adhesive and 0.5-2% of a lubricant.
4. The pharmaceutical composition comprising a phenylpyrimidinone hydrochloride according to claim 2 or 3, wherein:
the filler is at least one of lactose, corn starch, mannitol, sorbitol and microcrystalline cellulose; the disintegrant is at least one of low-substituted hydroxypropyl cellulose, croscarmellose sodium, carboxymethyl starch sodium and crospovidone; the adhesive is at least one of hydroxypropyl cellulose, hydroxypropyl methylcellulose and povidone; the lubricant is at least one of magnesium stearate, sodium stearyl fumarate, talcum powder and colloidal silicon dioxide.
5. The pharmaceutical composition comprising a phenylpyrimidinone hydrochloride according to any one of claims 2 to 4, wherein:
the filler is lactose and microcrystalline cellulose, the disintegrant is carboxymethyl starch sodium, the binder is povidone, and the lubricant is magnesium stearate.
6. The method of preparing a pharmaceutical composition comprising a phenylpyrimidinone hydrochloride according to any one of claims 1 to 5, comprising the steps of: mixing a compound of formula I-A and a pharmaceutically acceptable carrier.
7. A pharmaceutical formulation made from the pharmaceutical composition containing phenylpyrimidinone hydrochloride according to any one of claims 2 to 5, which is a tablet, capsule, granule, pill, powder, or dry suspension, preferably a tablet or capsule.
8. A method of preparing a pharmaceutical formulation according to claim 7, comprising the steps of:
(1) pulverizing the compound of formula I-A to a target particle size, sieving the filler, disintegrant, binder and lubricant;
(2) uniformly mixing the compound of formula I-A crushed in the step (1) and the sieved filler, disintegrant and adhesive to obtain a mixed material; or
Uniformly mixing the compound of formula I-A crushed in the step (1) with the sieved filler and disintegrant, and adding the sieved adhesive solution in the step (1) for granulation to obtain drug-containing granules;
(3) adding the lubricant sieved in the step (1) into the mixed material or the medicine-containing granules in the step (2), and uniformly mixing to obtain total mixed powder;
(4) and (4) tabletting or filling the total mixed powder in the step (3) into capsules.
9. Use of a pharmaceutical composition comprising a phenylpyrimidinone hydrochloride according to any one of claims 1 to 5 or a pharmaceutical formulation according to claim 7 in the manufacture of a medicament for the treatment and/or prevention of a disease and/or disorder associated with the PDE5 enzyme;
preferably, the diseases and/or conditions associated with the PDE5 enzyme include erectile dysfunction, pulmonary hypertension, female sexual dysfunction, premature labor, dysmenorrhea, benign prostatic hyperplasia, bladder outlet obstruction, incontinence, unstable and variant angina, hypertension, congestive heart failure, renal failure, atherosclerosis, stroke, peripheral vascular disease, raynaud's disease, inflammatory diseases, bronchitis, chronic asthma, allergic rhinitis, glaucoma, and disorders of bowel movement.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210079753.0A CN114344306B (en) | 2022-01-24 | 2022-01-24 | Pharmaceutical composition containing phenylpyrimidinone hydrochloride, pharmaceutical preparation containing pharmaceutical composition, preparation method and application of pharmaceutical composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210079753.0A CN114344306B (en) | 2022-01-24 | 2022-01-24 | Pharmaceutical composition containing phenylpyrimidinone hydrochloride, pharmaceutical preparation containing pharmaceutical composition, preparation method and application of pharmaceutical composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114344306A true CN114344306A (en) | 2022-04-15 |
| CN114344306B CN114344306B (en) | 2023-09-26 |
Family
ID=81094177
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210079753.0A Active CN114344306B (en) | 2022-01-24 | 2022-01-24 | Pharmaceutical composition containing phenylpyrimidinone hydrochloride, pharmaceutical preparation containing pharmaceutical composition, preparation method and application of pharmaceutical composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114344306B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102216279A (en) * | 2008-12-10 | 2011-10-12 | 上海特化医药科技有限公司 | Phenyl pyrimidone compounds, pharmaceutical compositions, preparation methods and uses thereof |
| WO2021208976A1 (en) * | 2020-04-17 | 2021-10-21 | 上海海雁医药科技有限公司 | Solid pharmaceutical preparation, preparation method therefor and use thereof |
-
2022
- 2022-01-24 CN CN202210079753.0A patent/CN114344306B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102216279A (en) * | 2008-12-10 | 2011-10-12 | 上海特化医药科技有限公司 | Phenyl pyrimidone compounds, pharmaceutical compositions, preparation methods and uses thereof |
| WO2021208976A1 (en) * | 2020-04-17 | 2021-10-21 | 上海海雁医药科技有限公司 | Solid pharmaceutical preparation, preparation method therefor and use thereof |
Non-Patent Citations (1)
| Title |
|---|
| "2017年浙江省春拍中科院上海分院科技成果投资路演推介会", 《今日科技》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114344306B (en) | 2023-09-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101699912B1 (en) | Pharmaceutical formulation comprising one or more fumaric acid esters in an erosion matrix | |
| CA2606510C (en) | Pharmaceutical preparation for oral administration comprising an imide compound | |
| CN106389371B (en) | tofacitinib citrate pharmaceutical composition | |
| TWI415633B (en) | Solid preparations containing enteric solid dispersions | |
| JP2009542647A (en) | Memantine pharmaceutical composition | |
| CA2714524A1 (en) | Tablet having improved elution properties | |
| EP3881833A1 (en) | Immediate-release tablets containing a drug and processes for forming the tablets | |
| US20140335176A1 (en) | Disintegrant-free delayed release doxylamine and pyridoxine formulation and process of manufacturing | |
| AU2019232937B2 (en) | Ceritinib formulation | |
| KR20160105044A (en) | Solid composite formulation for oral administration comprising ezetimibe and rosuvastatin | |
| CN114344306B (en) | Pharmaceutical composition containing phenylpyrimidinone hydrochloride, pharmaceutical preparation containing pharmaceutical composition, preparation method and application of pharmaceutical composition | |
| CN110787144A (en) | Film coated tablet containing hydrobromic acid vortioxetine and preparation method thereof | |
| CN113368073A (en) | Method for producing a pharmaceutical preparation for reducing blood uric acid levels | |
| US11458102B2 (en) | Acetaminophen preparation, and method for producing same | |
| CN111759817A (en) | Febuxostat-containing tablet and preparation method thereof | |
| CN113768889B (en) | Cilostazol-containing pharmaceutical composition and preparation method thereof | |
| EP3072529B1 (en) | Composition comprising vemurafenib and hpmc-as | |
| CN104000821B (en) | Oral double-layer tablet containing telmisartan and amlodipine besylate and preparation method thereof | |
| CN113925839B (en) | Metoprolol succinate sustained-release tablet and preparation method thereof | |
| WO2022042646A1 (en) | Lurasidone hydrochloride composition and preparation method therefor | |
| CN113368032A (en) | Pharmaceutical composition, oral solid preparation and preparation method and application thereof | |
| WO2017073738A1 (en) | Tablet having fexofenadine as effective component thereof | |
| CN115006400A (en) | Pharmaceutical composition containing piperazixil and preparation method thereof | |
| JP2019142814A (en) | Production method of febuxostat-containing tablet | |
| CN117357531A (en) | Pharmaceutical composition, preparation method and application 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 | ||
| CP03 | Change of name, title or address |
Address after: 215123 floor 8, building a, No. 108, Yuxin Road, Suzhou Industrial Park, Suzhou City, Jiangsu Province Patentee after: Suzhou Wangshan Wangshui Biopharmaceutical Co.,Ltd. Country or region after: China Patentee after: Wangshan wangshui (Lianyungang) Pharmaceutical Co.,Ltd. Address before: 215123 floor 8, building a, No. 108, Yuxin Road, Suzhou Industrial Park, Suzhou City, Jiangsu Province Patentee before: SUZHOU VIGONVITA LIFE SCIENCES Co.,Ltd. Country or region before: China Patentee before: Wangshan wangshui (Lianyungang) Pharmaceutical Co.,Ltd. |