CN113440491A - 一种坦度螺酮控释口崩片及其制备方法 - Google Patents
一种坦度螺酮控释口崩片及其制备方法 Download PDFInfo
- Publication number
- CN113440491A CN113440491A CN202110940106.XA CN202110940106A CN113440491A CN 113440491 A CN113440491 A CN 113440491A CN 202110940106 A CN202110940106 A CN 202110940106A CN 113440491 A CN113440491 A CN 113440491A
- Authority
- CN
- China
- Prior art keywords
- tandospirone
- controlled
- release
- orally disintegrating
- disintegrating tablet
- 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.)
- Pending
Links
- 238000013270 controlled release Methods 0.000 title claims abstract description 102
- CEIJFEGBUDEYSX-FZDBZEDMSA-N tandospirone Chemical compound O=C([C@@H]1[C@H]2CC[C@H](C2)[C@@H]1C1=O)N1CCCCN(CC1)CCN1C1=NC=CC=N1 CEIJFEGBUDEYSX-FZDBZEDMSA-N 0.000 title claims abstract description 95
- 229950000505 tandospirone Drugs 0.000 title claims abstract description 95
- 239000006191 orally-disintegrating tablet Substances 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- 238000000576 coating method Methods 0.000 claims abstract description 33
- 239000002245 particle Substances 0.000 claims abstract description 27
- 239000008187 granular material Substances 0.000 claims abstract description 12
- 239000000463 material Substances 0.000 claims description 44
- 239000007771 core particle Substances 0.000 claims description 33
- 239000011248 coating agent Substances 0.000 claims description 32
- 239000003826 tablet Substances 0.000 claims description 26
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 22
- 238000005507 spraying Methods 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 19
- 238000001035 drying Methods 0.000 claims description 13
- 238000002156 mixing Methods 0.000 claims description 13
- 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 12
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 12
- 239000008101 lactose Substances 0.000 claims description 12
- 235000019359 magnesium stearate Nutrition 0.000 claims description 11
- 229920002472 Starch Polymers 0.000 claims description 10
- 239000008107 starch Substances 0.000 claims description 10
- 235000019698 starch Nutrition 0.000 claims description 10
- 239000000945 filler Substances 0.000 claims description 9
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 8
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 8
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 8
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 8
- 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 8
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 8
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 8
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 8
- 108010011485 Aspartame Proteins 0.000 claims description 6
- 235000016623 Fragaria vesca Nutrition 0.000 claims description 6
- 235000011363 Fragaria x ananassa Nutrition 0.000 claims description 6
- 239000000605 aspartame Substances 0.000 claims description 6
- 235000010357 aspartame Nutrition 0.000 claims description 6
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 6
- 229960003438 aspartame Drugs 0.000 claims description 6
- 229960000913 crospovidone Drugs 0.000 claims description 6
- 239000007884 disintegrant Substances 0.000 claims description 6
- 239000000314 lubricant Substances 0.000 claims description 6
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 6
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 230000004584 weight gain Effects 0.000 claims description 6
- 235000019786 weight gain Nutrition 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000000796 flavoring agent Substances 0.000 claims description 5
- 235000013355 food flavoring agent Nutrition 0.000 claims description 5
- 239000001856 Ethyl cellulose Substances 0.000 claims description 4
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 4
- 239000000853 adhesive Substances 0.000 claims description 4
- 230000001070 adhesive effect Effects 0.000 claims description 4
- 229920001249 ethyl cellulose Polymers 0.000 claims description 4
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 4
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-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
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 238000005469 granulation Methods 0.000 claims description 3
- 230000003179 granulation Effects 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 229940085605 saccharin sodium Drugs 0.000 claims description 3
- 239000004925 Acrylic resin Substances 0.000 claims description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 2
- 239000004375 Dextrin Substances 0.000 claims description 2
- 229920001353 Dextrin Polymers 0.000 claims description 2
- 229920000881 Modified starch Polymers 0.000 claims description 2
- 239000004376 Sucralose Substances 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- 239000002253 acid Substances 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 2
- 235000013539 calcium stearate Nutrition 0.000 claims description 2
- 239000008116 calcium stearate Substances 0.000 claims description 2
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
- 235000019425 dextrin Nutrition 0.000 claims description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 2
- 239000000845 maltitol Substances 0.000 claims description 2
- 235000010449 maltitol Nutrition 0.000 claims description 2
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims description 2
- 229940035436 maltitol Drugs 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- 239000000113 methacrylic resin Substances 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
- 229940069328 povidone Drugs 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 229940083542 sodium Drugs 0.000 claims description 2
- 235000015424 sodium Nutrition 0.000 claims description 2
- OKODKVMXHLUQSW-JITBQSAISA-M sodium;(e)-4-hydroxy-4-oxobut-2-enoate;octadecanoic acid Chemical compound [Na+].OC(=O)\C=C\C([O-])=O.CCCCCCCCCCCCCCCCCC(O)=O OKODKVMXHLUQSW-JITBQSAISA-M 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 235000019408 sucralose Nutrition 0.000 claims description 2
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- 240000009088 Fragaria x ananassa Species 0.000 claims 1
- 239000012458 free base Substances 0.000 claims 1
- 239000008280 blood Substances 0.000 abstract description 13
- 210000004369 blood Anatomy 0.000 abstract description 13
- 208000019505 Deglutition disease Diseases 0.000 abstract description 5
- 239000000843 powder Substances 0.000 abstract description 4
- 238000001727 in vivo Methods 0.000 abstract description 3
- 239000003651 drinking water Substances 0.000 abstract description 2
- 235000020188 drinking water Nutrition 0.000 abstract description 2
- 210000003296 saliva Anatomy 0.000 abstract description 2
- 238000012423 maintenance Methods 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 38
- 229940079593 drug Drugs 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 239000007788 liquid Substances 0.000 description 18
- 230000000694 effects Effects 0.000 description 14
- 208000019901 Anxiety disease Diseases 0.000 description 10
- 238000005070 sampling Methods 0.000 description 10
- 238000000034 method Methods 0.000 description 8
- 239000008213 purified water Substances 0.000 description 8
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 8
- 238000007873 sieving Methods 0.000 description 8
- 210000000214 mouth Anatomy 0.000 description 7
- 239000000686 essence Substances 0.000 description 6
- 239000012467 final product Substances 0.000 description 6
- 230000002829 reductive effect Effects 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
- 241000220223 Fragaria Species 0.000 description 5
- 208000011688 Generalised anxiety disease Diseases 0.000 description 5
- 230000036506 anxiety Effects 0.000 description 5
- 208000029364 generalized anxiety disease Diseases 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 238000000889 atomisation Methods 0.000 description 4
- 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 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 229920003157 Eudragit® RL 30 D Polymers 0.000 description 3
- 229920003161 Eudragit® RS 30 D Polymers 0.000 description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000035699 permeability Effects 0.000 description 3
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- 210000001187 pylorus Anatomy 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000002249 anxiolytic agent Substances 0.000 description 2
- 230000000949 anxiolytic effect Effects 0.000 description 2
- 230000008499 blood brain barrier function Effects 0.000 description 2
- 210000001218 blood-brain barrier Anatomy 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 230000001055 chewing effect Effects 0.000 description 2
- 239000003405 delayed action preparation Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 239000013022 formulation composition Substances 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- 210000004877 mucosa Anatomy 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 230000001242 postsynaptic effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000018 receptor agonist Substances 0.000 description 2
- 229940044601 receptor agonist Drugs 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000009747 swallowing Effects 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 241001391944 Commicarpus scandens Species 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 206010013911 Dysgeusia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000037490 Medically Unexplained Symptoms Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920003081 Povidone K 30 Polymers 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000004630 mental health Effects 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 230000000474 nursing effect Effects 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 210000002820 sympathetic nervous system Anatomy 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Images
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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nutrition Science (AREA)
- Neurology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Zoology (AREA)
- Inorganic Chemistry (AREA)
- Biomedical Technology (AREA)
- Physiology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明涉及一种坦度螺酮控释口崩片及其制备方法,主要包括采用粉末包衣法制备坦度螺酮控释颗粒,再经粉末直接压片制成口崩片。其特点是服用方便,在不需要饮水的条件下,该制剂遇唾液快速崩解成控释颗粒,适合老年人和儿童等吞咽困难人群的给药,患者顺应性高,且在体内接近恒定速率释放坦度螺酮,并维持稳定的血药浓度,具有显著的临床价值。
Description
技术领域
本发明涉及一种坦度螺酮控释口崩片及其制备方法,属于药物制剂领域。
背景技术
广泛性焦虑症(generalized anxiety disorder,GAD)是最常见的焦虑症。据《精神障碍诊断和统计手册》第5版,GAD定义为以过度的、广泛的、难以控制的焦虑或担心许多活动或事件至少6个月为特征的,与精神病学相联系的慢性、复发性疾病。2010年《焦虑障碍防治指南》报道,世界范围内普通人群中年患病率1.9%~5.1%,在成人中的终身患病率估计为4.1%~6%。近年来,我国GAD患者呈不断上升趋势,患者心理健康、社会能力和生活质量受到严重影响。
坦度螺酮(Tandospirone)是由日本住友制药株式会社研制的氮杂螺酮类抗焦虑药,其作用机制完全不同于传统的安定类药物,无成瘾性、耐受性、戒断反应和损害认知功能的作用。坦度螺酮能高度选择性与5-HT1A受体结合,激动突触后膜的5-HT1A受体,而抑制亢进的5-HT能神经活动,使5-羟色胺与突触后膜的5-HT1A和5-HT2A受体的结合恢复平衡状态,从而发挥抗焦虑作用。坦度螺酮还可通过激动海马回的5-HT1A受体,抑制海马部形成的焦虑信号,同时激动中隔的5-HT1A受体,进而抑制焦虑信号由中隔传至下丘脑,最终抑制焦虑所导致的交感神经系统所产生的异常活动,抑制末梢躯体症状的表现。该药临床上主要用于广泛性焦虑症,如伴发焦虑的高血压患者和伴发焦虑的肠易激综合征患者以及慢性阻塞性肺病患者焦虑症状的治疗。
目前,市售的主要为坦度螺酮枸橼酸盐,其20mg规格片剂的药代动力学特点:口服吸收迅速,0.8~1.4小时后达最高血药浓度(Cmax:2.9~3.2ng/mL),其半衰期为1.2~1.4小时,基本不受食物影响且无蓄积性。但现在市售的坦度螺酮制剂具有以下的问题:(1)临床使用时需要每日服用3次(10mg/次),这种频繁的给药方式无疑会导致病人服用顺应性差。另外,坦度螺酮属于作用于中枢神经系统类药物,口服给药通过胃肠道吸收入血进入体循环,然后通过血脑屏障入脑后再分布到相应的靶点才能发挥抗焦虑或抗抑郁作用。血脑屏障为大脑的防御性屏障,对物质的透过有严格的限制条件,药物要透过这层屏障,除了药物本身的渗透性外,还受血药浓度的制约。(2)坦度螺酮半衰期极短,血药浓度峰谷现象明显,从而很难长时间维持脑内外的药物浓度差,从而影响治疗效果。(3)现有的坦度螺酮制剂包括普通片剂和胶囊,但对于老人和儿童等吞咽困难的特殊病人服用非常不方便。
1986年国外研发了口腔崩解片(简称口崩片),20世纪90年代末该剂型才引起广泛的关注。与普通片剂和胶囊相比,该剂型无需用水也无需咀嚼,药物置于舌上,遇唾液快速崩解后,借助吞咽动作入胃起效,也可以置于舌下,迅速崩解后药物通过粘膜吸收起效。该制剂对口腔粘膜无刺激性,给药方便,从而提高患者的服药依从性,也可减少护理工作负担。适合老年人和儿童等吞咽困难患者服用。
控释制剂是指用药后能在机体内以接近恒定速率释放药物,使药物在较长时间内维持有效血药浓度的药物给药系统。多单元控释制剂在疗效方面更具有优势,不仅体积小,易于吞服,且在胃肠道的转运不受食物输送节律的影响(直径小于2mm的颗粒可通过闭合的幽门,因此吸收一般不受胃排空的影响)同时又具有服用次数少,避免血药浓度峰谷现象,提高疗效,降低不良反应。
专利CN1915233A、CN104997740A分别公开坦度螺酮口崩制剂和分散片的处方组成及其制备方法,虽然可以解决特殊人群用药困难的问题,但由于其为普通口服固体制剂,不能调控药物在体内的释放速度,因此不能解决给药频繁、血药浓度峰谷现象等问题。
专利CN109847008A、CN1899287A公开了一种治疗焦虑症的缓释药物组合物及其制备方法,虽然可以改善普通制剂给药频繁的问题,但由于其缓释效果有限(12h内药物在体外完全释放),故给药次数只能从3次/天减少到2次/天,而不能1次/天给药。
专利CN106619481A公开了一种长效的5-HT1A受体激动剂及其制备方法,虽然可以解决给药频繁的问题,但由于其为骨架缓释片,容易受到幽门直径限制,通过幽门时可能发生形变,导致释药面积增大或不可控,进而可能导致药物突释的风险增大。
专利CN106344519A、CN106176659A分别公开了坦度螺酮肠溶微丸和肠溶片的处方组成及其制备方法,但其目的是为了减少坦度螺酮对胃的刺激,而不能解决或改善上述所提到的坦度螺酮普通口服固体制剂所存在的问题。
专利US5185158、US5246711、US5246710、US5330762、US5858407、US5688518、WO9416699A1中公开了一种有孔型枸橼酸坦度螺酮渗透泵型控释制剂,包括双层片芯、包衣膜和释药孔。其中片芯由含药层和助推层组成,尽管该制剂释药相对平稳,但释药孔容易被堵塞或过大,导致无规则释药使疗效降低或产生较大副作用的缺陷。CN104706614A公开了坦度螺酮微孔渗透泵制剂,虽然不会出现释药孔被堵塞或过大的问题,但该渗透泵制剂需要进行半透膜包衣,会排放大量的丙酮和异丙醇,对环境污染极大,且需要特殊装置或设备对其处理,生产成本也相应增高。因为环保和安全的因素,有机溶剂尤其是纯有机溶剂越来越不建议在药品生产中使用,应尽量避免。
综上所述,现有的坦度螺酮制剂存在给药频繁、血药浓度峰谷现象明显,且不利于老年人和儿童等吞咽困难患者服用等不足。
发明内容
本发明的目的是为了克服以上现有的坦度螺酮制剂的不足,提供了一种制备工艺简单、服用方便、具有控释作用的坦度螺酮控释口崩片及其制备方法。本发明先采用粉末包衣技术和具有控释作用的辅料,制备坦度螺酮控释颗粒,再利用直接压片辅料压片制得口崩片。
本发明通过以下技术方案来实现。
本发明提供了一种坦度螺酮控释口崩片,其特征在于,包含以控释颗粒存在的活性成分,以及药学上可接受的及可改善片剂口感的药用辅料,其中坦度螺酮的单位剂量为10~60mg,优选10mg和20mg。
本发明涉及的坦度螺酮控释口崩片,其特征在于,所述的坦度螺酮可以为游离碱或弱酸盐。
本发明涉及的坦度螺酮控释口崩片,其特征在于,其重量组成含有坦度螺酮控释颗粒10%~80%。
本发明涉及的坦度螺酮控释口崩片,其特征在于,所述的坦度螺酮控释颗粒包括核心粒子和控释层。
本发明涉及的坦度螺酮控释口崩片,其特征在于:所述的核心粒子材料选自微晶纤维素、淀粉、乳糖中的至少一种,优选乳糖;所述核心粒子粘合剂选自聚维酮、羟丙甲纤维素、羟丙基纤维素中的一种或几种,优选羟丙甲纤维素;所述的控释层包衣材料选自乙基纤维素、聚丙烯酸树脂、甲基丙烯酸树脂、羟丙基纤维素中的一种或几种。
本发明涉及的坦度螺酮控释口崩片,其特征在于:所述的核心粒子的粒径为50~400μm,优选100~200μm;所述的控释颗粒的粒径为100~600μm,优选150~400μm。
本发明涉及的坦度螺酮控释口崩片,其特征在于,所述的控释颗粒包衣增重为30~200%,优选100%。
本发明涉及的坦度螺酮控释口崩片,其特征在于,所述的药用辅料包括填充剂、崩解剂、矫味剂、润滑剂;其中填充剂选自淀粉、微晶纤维素、乳糖、糊精、甘露醇、预胶化淀粉中的一种或几种;崩解剂选自低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠、交联羧甲基淀粉钠、羧甲基淀粉钠、干淀粉中的一种或几种;矫味剂选自糖精钠、三氯蔗糖、阿斯巴甜、木糖醇、麦芽糖醇、橘子香精、草莓香精中的一种或几种;润滑剂选自硬脂酸镁、硬脂酸钙、硬脂酸富马酸钠、硬脂酸镁中的一种或几种。
本发明涉及的坦度螺酮控释口崩片,其制备方法包括如下步骤:
(1)核心粒子制备:配制粘合剂溶液,备用;将坦度螺酮与填充剂混合均匀后置于流化床中,将已制备的粘合剂喷入流化床中进行造粒,干燥。
(2)控释颗粒制备:将控释包衣材料分散或溶解于溶剂中,搅拌均匀后,对步骤(1)所制得的核心粒子进行控释包衣,干燥。
(3)控释口崩片制备:将步骤(2)制得的坦度螺酮控释颗粒与填充剂、崩解剂、矫味剂和润滑剂混合均匀后,压片即得。
本发明至少包括以下有益效果:
(1)本发明采用缓控释技术,将坦度螺酮制成控释颗粒,可以减缓药物在体内释放速度(达24h释药),使药物在较长时间内维持有效的血药浓度,从而减小给药频率,提高依从性,避免血药浓度峰谷现象,降低毒副反应。
(2)本发明基于药物控释颗粒并借助于口崩片无需饮水、口内崩解吞咽服药的原理,为特殊患者提供便利的给药方式。
(3)本发明的制备方法简单,易于工业化大规模制备,工艺重现性好,得到的产品可有效的控制药物的释放速度,且对胃肠道粘膜基本无刺激作用,具有较好的经济和社会效益。
附图说明
图1为实施例1~3的坦度螺酮控释口崩片的释放曲线图;
图2为实施例1和实施例4的坦度螺酮控释口崩片的释放曲线图;
图3为实施例1和实施例5的坦度螺酮控释口崩片的释放曲线图;
图4为实施例14~16制备的坦度螺酮控释口崩片的释放曲线;
图5为实施例1和实施例17的药时曲线图。
具体实施方式
以下典型实施例用来举例说明本发明,在本领域内的技术人员对本发明所做的简单替换或改进等均属于本发明所保护的技术方案之内。
下面结合具体实施例进一步说明本发明的技术方案,实施例所描述的具体的物料配比、工艺条件及其结果仅用于说明本发明,而不应当也不会限定权利要求书所详细描述的本发明。
实施例1~4:
坦度螺酮控释口崩片的处方组成和处方量:
注:[1]指含坦度螺酮的量;[2]按其固含量计。
制备工艺:
将羟丙甲纤维素溶于纯化水中,备用。将枸橼酸坦度螺酮与乳糖混合均匀后置于流化床中,调节风量使物料处于流化状态,调节进风温度40~70℃,当物料温度达40℃时开始喷液(羟丙甲纤维素溶液),调节喷速及雾化压力,控制物料温度30~40℃,进行核心粒子制备,喷液结束后,调节进风温度65~75℃,控制物料温度45℃~50℃继续干燥15~40分钟,取样检测水分合格后过筛,得到核心粒子。
核心粒子制备完毕后,将Eudragit RS30D、Eudragit RL30D、聚乙二醇6000、滑石粉、溶解或分散于纯化水中,搅拌均匀后制得控释层包衣液,在同一个流化床中,调节合适的雾化压力和喷液速度,调节进风温度60~70℃,控制物料温度为30~42℃,对所得核心粒子进行控释层包衣。包衣完毕后,调节进风温度50~65℃,控制物料温度30℃~45℃继续干燥15分钟,取样检测水分合格后过筛,得到控释颗粒。
将上述枸橼酸坦度螺酮载药控释颗粒与微晶纤维素、交联聚维酮、草莓香精、阿斯巴甜和硬脂酸镁混合均匀后,压片即得最终产品。
实施例5:
坦度螺酮控释口崩片的处方组成和处方量:
注:[1]指含坦度螺酮的量。
制备工艺:
将羟丙甲纤维素溶于纯化水中,备用。将枸橼酸坦度螺酮与乳糖混合均匀后置于流化床中,调节风量使物料处于流化状态,调节进风温度40~70℃,当物料温度达40℃时开始喷液(羟丙甲纤维素溶液),调节喷速及雾化压力,控制物料温度30~40℃,进行核心粒子制备。喷液结束后,调节进风温度65~75℃,控制物料温度45℃~50℃继续干燥15~40分钟,取样检测水分合格后过筛,得到核心粒子。
核心粒子制备完毕后,将乙基纤维素、聚维酮K30分散于乙醇中,加入滑石粉,搅拌均匀后制得控释层包衣液。在同一个流化床中,调节合适的雾化压力和喷液速度,调节进风温度30~45℃,控制物料温度为20~32℃,对所得核心粒子进行控释层包衣,包衣完毕后,调节进风温度50~65℃,控制物料温度30℃~45℃继续干燥15分钟,取样检测水分合格后过筛,得到控释颗粒。
将上述枸橼酸坦度螺酮载药控释颗粒与微晶纤维素、交联聚维酮、草莓香精、阿斯巴甜和硬脂酸镁混合均匀后,压片即得最终产品。
实施例6~10:
坦度螺酮控释口崩片的处方组成和处方量:
注:[1]指含坦度螺酮的量;[2]按其固含量计。
制备工艺:
将羟丙甲纤维素溶于纯化水中,备用。将坦度螺酮与乳糖混合均匀后置于流化床中,调节风量使物料处于流化状态,调节进风温度40~70℃,当物料温度达40℃时开始喷液(羟丙甲纤维素溶液),调节喷速及雾化压力,控制物料温度30~40℃,进行核心粒子制备。喷液结束后,调节进风温度65~75℃,控制物料温度45℃~50℃继续干燥15~40分钟,取样检测水分合格后过筛,得到核心粒子。
核心粒子制备完毕后,将Eudragit RS30D、Eudragit RL30D、聚乙二醇6000、滑石粉、溶解或分散于纯化水中,搅拌均匀后制得控释层包衣液。在同一个流化床中,调节合适的雾化压力和喷液速度,调节进风温度60~75℃,控制物料温度为30~42℃,对所得核心粒子进行控释层包衣。包衣完毕后,调节进风温度50~65℃,控制物料温度30℃~45℃继续干燥15分钟,取样检测水分合格后过筛,得到控释颗粒。
将上述枸橼酸坦度螺酮载药控释颗粒与填充剂、崩解剂、草莓香精、阿斯巴甜和硬脂酸镁混合均匀后,压片即得最终产品。
实施例11~13:
坦度螺酮控释口崩片的处方组成和处方量:
注:[1]指含坦度螺酮的量;[2]按其固含量计。
制备工艺:
将羟丙甲纤维素溶于纯化水中,备用。将坦度螺酮与乳糖混合均匀后置于流化床中,调节风量使物料处于流化状态,调节进风温度40~70℃,当物料温度达40℃时开始喷液(羟丙甲纤维素溶液),调节喷速及雾化压力,控制物料温度30~40℃,进行核心粒子制备。喷液结束后,调节进风温度65~75℃,控制物料温度45℃~50℃继续干燥15~40分钟,取样检测水分合格后过筛,得到核心粒子。
核心粒子制备完毕后,将Eudragit RS30D、Eudragit RL30D、聚乙二醇6000、滑石粉、溶解或分散于纯化水中,搅拌均匀后制得控释层包衣液。在同一个流化床中,调节合适的雾化压力和喷液速度,调节进风温度60~75℃,控制物料温度为30~42℃,对所得核心粒子进行控释层包衣。包衣完毕后,调节进风温度50~65℃,控制物料温度30℃~45℃继续干燥15分钟,取样检测水分合格后过筛,得到控释颗粒。
将上述坦度螺酮载药控释颗粒与微晶纤维素、交联聚维酮、矫味剂和硬脂酸镁混合均匀后,压片即得最终产品。
实施例14~16:
项目 | 实施例14 | 实施例15 | 实施例16 |
核心粒子粒径(μm) | 50-100 | 100-200 | 200-400 |
控释颗粒粒径(μm) | 100-150 | 150-400 | 400-600 |
按照实施例1处方工艺制备核心粒子,并筛分出符合要求的核心粒子,备用。将核心颗粒进行控释包衣后筛分出符合要求的控释颗粒。将控释颗粒与微晶纤维素、交联聚维酮、草莓香精、阿斯巴甜和硬脂酸镁混合均匀后,压片即得最终产品。
实施例17:
坦度螺酮片的处方组成和处方量:
组成 | 用量/g,1000片 |
枸橼酸坦度螺酮 | 20.00<sup>[1]</sup> |
乳糖 | 50.00 |
淀粉 | 5.00 |
羧甲基纤维素钙 | 3.00 |
聚乙烯醇 | 2.00 |
硬脂酸镁 | 2.00 |
注:[1]指含坦度螺酮的量。
制备工艺:
将聚乙烯醇溶于纯化水中,备用。将坦度螺酮、乳糖、淀粉、羧甲基纤维素钙置于流化床中,调节风量是物料处于流化状态,调节进风温度40~70℃,当物料温度达40℃时开始喷液(聚乙烯醇溶液),调节喷速及雾化压力,控制物料温度30~40℃,进行流化床制粒,继续干燥15~40分钟,取样检测水分合格后,得到坦度螺酮颗粒。
将上述坦度螺酮颗粒与硬脂酸镁混合均匀后,压片即得最终产品。
实施例18:口感测试实验:
坦度螺酮控释口崩片口感对比结果:
实施例 | 口腔崩解时间/秒 | 硬物感 | 口腔感受 | 甜度 |
实施例1 | 40 | 1 | 1 | 4 |
实施例6 | 42 | 1 | 2 | 4 |
实施例7 | 40 | 1 | 2 | 4 |
实施例8 | 80 | 4 | 5 | 4 |
实施例9 | 30 | 3 | 4 | 4 |
实施例10 | 41 | 1 | 1 | 4 |
实施例11 | 41 | 1 | 1 | 6 |
实施例12 | 40 | 1 | 1 | 2 |
实施例13 | 42 | 1 | 1 | 4 |
口腔崩解评价采用志愿者尝试服用的方式。口感尝试后的样品不进行吞咽,评判标准:
口腔崩解时间:受试者事先水漱口,然后将片置于舌面上,开始计时,期间不用水,不允许咀嚼,至片剂完全崩解停止计时;
硬物感:1~10分,1分为完全无硬物感,10分为硬物感严重、令人不适。
口腔感受:1~10分,1分为口感细腻,10分为口感粗糙、有沙砾感、令人不适。
甜度:1~10分,1分为没有甜度,10分为非常甜。
口感测试每次3片,测试结束对3片结果进行综合打分。
实验研究发现,实施例6、7中的甘露醇会引起口感略差;实施例8中崩解剂用量过低,口腔崩解时间较长,硬物感增强,口感变差;实施例9中崩解剂用量过高,部分崩解后团聚从而产生砂砾感和硬物感;实施例11加入糖精钠后甜度增加;实施例12中未加入香精后,口味欠佳。以上结果表明不同成分、用量的配比可改善片剂的口感及甜度。
实施例19:释放曲线的检测:
方法:按照《中国药典》2020年版四部通则(0931)溶出度与释放度测定法,采用第二法(桨法)进行测定:温度37.0℃±0.5℃,pH6.8磷酸盐缓冲液900ml,50rpm,取样:1h、2h、4h、6h、8h、10、12h、16h、20h、24h时分别取液2ml过滤(0.45μm滤膜),同时补充2ml相同温度介质。检测方法:HPLC法。
实施例1~3制备的坦度螺酮控释口崩片的释放曲线如附图1所示。
结果表明:控释包衣增重越多,衣膜透水性越低,药物释放速度变慢;包衣增重减少,衣膜变薄,通透性增加导致药物释放速度变快;包衣增重从60%到150%,其对应的药物释放曲线变化程度较小,其原因可能与包衣液处方中致孔剂的比例变化有关。
实施例1、4制备的的坦度螺酮控释口崩片的释放曲线如附图2所示。
结果表明:包衣增重减少,药物的释放速度显著变快。
实施例1、5制备的的坦度螺酮控释口崩片的释放曲线如附图3所示。
结果表明:实施例5将包衣控释材料更换乙基纤维素也可以达到实施例1相似的药物释放速度。
实施例14~16制备的坦度螺酮控释口崩片的释放曲线如附图4所示。
结果表明:相同的包衣增重,核心颗粒越大,包衣后控释颗粒越大,压片后片剂的释放速度越慢;当粒径达到一定程度,压片过程容易出现膜的破裂,从而出现突释现象。
实施例20:动物药代动力学实验
取比格犬12只,雌雄各半,体重(10~12)kg,随机分为2组,给药前禁食12h,1片/只给药。静脉取血,检测血药浓度,计算药代动力学参数。
控释口崩片与普通片药代动力学参数比较如下:
T<sub>max</sub>(h) | C<sub>max</sub>(ng/ml) | AUC(ng.h/ml) | |
实施例1 | 7.8±2.4<sup>[1]</sup> | 2.2±0.6<sup>[1]</sup> | 92.6±15.6 |
实施例17 | 1.5±0.6 | 6.8±1.3 | 74.8±10.5 |
注:[1]与实施例17的结果有统计学差异(p<0.05)。
实施例1和实施例17所制得的坦度螺酮制剂的药时曲线如附图5所示。
药时曲线及药代动力学参数比较结果表明:控释口崩片与普通片相比达峰时间显著延长(Tmax)且有效作用时间也显著延长,峰浓度(Cmax)显著下降,曲线下面积(AUC)显著增大。
上述试验说明,对本领域技术人员来说,本发明是将坦度螺酮制备成控释口崩片,可以克服普通制剂频繁给药的问题,降低血药浓度峰谷现象,从而提高安全性。同时为老年人和儿童等吞咽困难的患者的用药提供便利。为了达到这个目的,本发明采用了粉末包衣技术及口崩片技术相结合,选择合适的辅料及配比达到最佳恒定的释药速度。虽然各控释辅料的性质是一定的,但是由于坦度螺酮的特殊化学物理性质,选用何种辅料,以及辅料何种用量,能达到最佳控释效果,能尽量最大限度减少控释辅料用量是不可预知的。各种控释辅料及压片辅料与坦度螺酮采用何种配比能较好地达到24小时的控释效果,也是不可预知的。上述两点对于本领域技术人员来说,都是不是显而易见的。本发明制备的控释口崩片制剂为临床治疗焦虑提供了一种新的选择,同时也为特殊人群的用药提供了方便。
Claims (9)
1.一种坦度螺酮控释口崩片,其特征在于,包含以控释颗粒存在的活性成分,以及药学上可接受的及可改善片剂口感的药用辅料,其中坦度螺酮的单位剂量为10~60mg,优选10mg和20mg。
2.根据权利要求1所述的坦度螺酮控释口崩片,其特征在于,所述的坦度螺酮可以为游离碱或弱酸盐。
3.根据权利要求1所述的坦度螺酮控释口崩片,其特征在于,其重量组成含有坦度螺酮控释颗粒10%~80%。
4.根据权利要求1~3所述的坦度螺酮控释口崩片,其特征在于,所述的坦度螺酮控释颗粒包括核心粒子和控释层。
5.根据权利要求1~4所述的坦度螺酮控释口崩片,其特征在于:所述的核心粒子材料选自微晶纤维素、淀粉、乳糖中的至少一种,优选乳糖;所述核心粒子粘合剂选自聚维酮、羟丙甲纤维素、羟丙基纤维素中的一种或几种,优选羟丙甲纤维素;所述的控释层包衣材料选自乙基纤维素、聚丙烯酸树脂、甲基丙烯酸树脂、羟丙基纤维素中的一种或几种。
6.根据权利要求1~4所述的坦度螺酮控释口崩片,其特征在于:所述的核心粒子的粒径为50~400μm,优选100~200μm;所述的控释颗粒的粒径为100~600μm,优选150~400μm。
7.根据权利要求1~4所述的坦度螺酮控释口崩片,其特征在于,所述的控释颗粒包衣增重为30~200%,优选100%。
8.根据权利要求1所述的坦度螺酮控释口崩片,其特征在于,所述的药用辅料包括填充剂、崩解剂、矫味剂、润滑剂;其中填充剂选自淀粉、微晶纤维素、乳糖、糊精、甘露醇、预胶化淀粉中的一种或几种;崩解剂选自低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠、交联羧甲基淀粉钠、羧甲基淀粉钠、干淀粉中的一种或几种;矫味剂选自糖精钠、三氯蔗糖、阿斯巴甜、木糖醇、麦芽糖醇、橘子香精、草莓香精中的一种或几种;润滑剂选自硬脂酸镁、硬脂酸钙、硬脂酸富马酸钠、硬脂酸镁中的一种或几种。
9.根据权利要求1~8所述的坦度螺酮控释口崩片,其制备方法包括如下步骤:
(1)核心粒子制备:配制粘合剂溶液,备用;将坦度螺酮与填充剂混合均匀后置于流化床中,将已制备的粘合剂喷入流化床中进行造粒,干燥。
(2)控释颗粒制备:将控释包衣材料分散或溶解于溶剂中,搅拌均匀后,对步骤(1)所制得的核心粒子进行控释包衣,干燥。
(3)控释口崩片制备:将步骤(2)制得的坦度螺酮控释颗粒与填充剂、崩解剂、矫味剂和润滑剂混合均匀后,压片即得。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110940106.XA CN113440491A (zh) | 2021-08-17 | 2021-08-17 | 一种坦度螺酮控释口崩片及其制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110940106.XA CN113440491A (zh) | 2021-08-17 | 2021-08-17 | 一种坦度螺酮控释口崩片及其制备方法 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN113440491A true CN113440491A (zh) | 2021-09-28 |
Family
ID=77818690
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110940106.XA Pending CN113440491A (zh) | 2021-08-17 | 2021-08-17 | 一种坦度螺酮控释口崩片及其制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN113440491A (zh) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1899287A (zh) * | 2006-07-19 | 2007-01-24 | 四川科瑞德制药有限公司 | 一种治疗焦虑症的缓释药物组合物及其制备方法 |
CN1915233A (zh) * | 2006-08-30 | 2007-02-21 | 四川科瑞德制药有限公司 | 一种治疗焦虑症的药物组合物及其口崩制剂 |
CN112315927A (zh) * | 2020-11-04 | 2021-02-05 | 南京康川济医药科技有限公司 | 一种帕利哌酮缓释口崩片及其制备方法 |
CN113018271A (zh) * | 2019-12-25 | 2021-06-25 | 四川科瑞德制药股份有限公司 | 一种坦度螺酮药物组合物及其制备方法和用途 |
-
2021
- 2021-08-17 CN CN202110940106.XA patent/CN113440491A/zh active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1899287A (zh) * | 2006-07-19 | 2007-01-24 | 四川科瑞德制药有限公司 | 一种治疗焦虑症的缓释药物组合物及其制备方法 |
CN1915233A (zh) * | 2006-08-30 | 2007-02-21 | 四川科瑞德制药有限公司 | 一种治疗焦虑症的药物组合物及其口崩制剂 |
CN113018271A (zh) * | 2019-12-25 | 2021-06-25 | 四川科瑞德制药股份有限公司 | 一种坦度螺酮药物组合物及其制备方法和用途 |
CN112315927A (zh) * | 2020-11-04 | 2021-02-05 | 南京康川济医药科技有限公司 | 一种帕利哌酮缓释口崩片及其制备方法 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5053865B2 (ja) | 口腔内崩壊性固形製剤の製造法 | |
CA2585363C (en) | Taste-masked multiparticulate pharmaceutical compositions comprising a drug-containing core particle and a solvent-coacervated membrane | |
AU2010324835B2 (en) | Compressible-coated pharmaceutical compositions and tablets and methods of manufacture | |
JP6173521B2 (ja) | ナルブフィンを含有する製剤及びそれらの使用 | |
KR101125268B1 (ko) | 구강 분산성 다중층 정제 | |
CN103429223A (zh) | 口腔分散片 | |
JP5813391B2 (ja) | 粒子製剤の製造方法 | |
WO2013139266A1 (zh) | 含芬特明和托吡酯的联合产品及其制备方法 | |
KR20090014081A (ko) | 활성성분의 코팅막이 보호되는 구강내붕해제형을 제조하기위한 조성물 | |
EP1911444A1 (en) | Drug-containing coated fine particle for intrabuccally disintegrating preparation and method of producing the same | |
CN112426408B (zh) | 一种褪黑素组合物及其制备工艺 | |
WO2003015758A1 (fr) | Micro-pastilles a liberation prolongee et procede permettant leur production | |
US7815939B2 (en) | Coated fine particles containing drug for intrabuccally fast disintegrating dosage forms | |
CN113440491A (zh) | 一种坦度螺酮控释口崩片及其制备方法 | |
KR20210003323A (ko) | 탐수로신 또는 이의 염산염 함유 제약 조성물 및 이의 제조방법 | |
CA3216586A1 (en) | Prolonged-release pharmaceutical composition for oral administration of sultiame | |
KR20220085746A (ko) | 염산 클로미프라민의 제어 방출을 위한 이중정 및 이의 제조방법 | |
KR100341664B1 (ko) | 제어방출형 아미트리프틸린 과립 및 그의 제조방법 | |
CN117355296A (zh) | 用于口服施用舒噻美的延长释放药物组合物 | |
CN117797105A (zh) | 一种奥卡西平咀嚼片及其制备方法 | |
WO2010123440A1 (en) | Pharmaceutical composition comprising 4-amino-8-(2-fluoro-6-methoxy-phenyl)-n- propylcinnoline-3-carboxamide hydrogen sulphate and rate-controlling polymer |
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 | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20210928 |
|
RJ01 | Rejection of invention patent application after publication |