CN114652689A - Tadalafil freeze-dried flash-release tablet and preparation process thereof - Google Patents
Tadalafil freeze-dried flash-release tablet and preparation process thereof Download PDFInfo
- Publication number
- CN114652689A CN114652689A CN202210198275.5A CN202210198275A CN114652689A CN 114652689 A CN114652689 A CN 114652689A CN 202210198275 A CN202210198275 A CN 202210198275A CN 114652689 A CN114652689 A CN 114652689A
- Authority
- CN
- China
- Prior art keywords
- tadalafil
- freeze
- release tablet
- flash
- pullulan
- 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.)
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Links
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 title claims abstract description 93
- 229960000835 tadalafil Drugs 0.000 title claims abstract description 93
- 238000002360 preparation method Methods 0.000 title abstract description 21
- 239000004373 Pullulan Substances 0.000 claims abstract description 68
- 229920001218 Pullulan Polymers 0.000 claims abstract description 68
- 235000019423 pullulan Nutrition 0.000 claims abstract description 68
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 21
- 229930195725 Mannitol Natural products 0.000 claims abstract description 21
- 239000000594 mannitol Substances 0.000 claims abstract description 21
- 235000010355 mannitol Nutrition 0.000 claims abstract description 21
- 238000004108 freeze drying Methods 0.000 claims abstract description 15
- 239000000853 adhesive Substances 0.000 claims abstract description 12
- 230000001070 adhesive effect Effects 0.000 claims abstract description 12
- 239000011230 binding agent Substances 0.000 claims abstract description 11
- 235000003599 food sweetener Nutrition 0.000 claims abstract description 10
- 239000003765 sweetening agent Substances 0.000 claims abstract description 10
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 7
- 239000007788 liquid Substances 0.000 claims description 63
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
- 239000007864 aqueous solution Substances 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 13
- 230000001804 emulsifying effect Effects 0.000 claims description 12
- 150000004676 glycans Chemical class 0.000 claims description 11
- 229920001282 polysaccharide Polymers 0.000 claims description 11
- 239000005017 polysaccharide Substances 0.000 claims description 11
- 239000004376 Sucralose Substances 0.000 claims description 10
- 235000019408 sucralose Nutrition 0.000 claims description 10
- 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 10
- 238000007710 freezing Methods 0.000 claims description 8
- 230000008014 freezing Effects 0.000 claims description 8
- 238000005520 cutting process Methods 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 238000004806 packaging method and process Methods 0.000 claims description 7
- 238000011049 filling Methods 0.000 claims description 6
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 3
- 238000004945 emulsification Methods 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 claims description 2
- 108010011485 Aspartame Proteins 0.000 claims description 2
- 239000004375 Dextrin Substances 0.000 claims description 2
- 229920001353 Dextrin Polymers 0.000 claims description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 2
- 239000004384 Neotame Substances 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- 235000010358 acesulfame potassium Nutrition 0.000 claims description 2
- 229960004998 acesulfame potassium Drugs 0.000 claims description 2
- 239000000619 acesulfame-K Substances 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
- 239000000605 aspartame Substances 0.000 claims description 2
- 235000010357 aspartame Nutrition 0.000 claims description 2
- 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 2
- 229960003438 aspartame Drugs 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 238000007872 degassing Methods 0.000 claims description 2
- 235000019425 dextrin Nutrition 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 2
- 235000019412 neotame Nutrition 0.000 claims description 2
- HLIAVLHNDJUHFG-HOTGVXAUSA-N neotame Chemical compound CC(C)(C)CCN[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 HLIAVLHNDJUHFG-HOTGVXAUSA-N 0.000 claims description 2
- 108010070257 neotame Proteins 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 38
- 230000000694 effects Effects 0.000 abstract description 16
- 238000002474 experimental method Methods 0.000 abstract description 10
- 239000003826 tablet Substances 0.000 description 44
- 229940079593 drug Drugs 0.000 description 24
- 238000010521 absorption reaction Methods 0.000 description 15
- 210000004877 mucosa Anatomy 0.000 description 15
- 238000003756 stirring Methods 0.000 description 14
- 238000012360 testing method Methods 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 230000004907 flux Effects 0.000 description 11
- 210000002919 epithelial cell Anatomy 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 8
- 229920000053 polysorbate 80 Polymers 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000000693 micelle Substances 0.000 description 6
- 210000000214 mouth Anatomy 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 230000035699 permeability Effects 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- 230000009471 action Effects 0.000 description 5
- 239000011248 coating agent Substances 0.000 description 5
- 238000000576 coating method Methods 0.000 description 5
- 210000000981 epithelium Anatomy 0.000 description 5
- 238000010579 first pass effect Methods 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000007789 sealing Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000009849 vacuum degassing Methods 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 208000010228 Erectile Dysfunction Diseases 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000000502 dialysis Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 201000001881 impotence Diseases 0.000 description 4
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 3
- -1 1, 3-benzodioxol-5-yl Chemical group 0.000 description 3
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 3
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 3
- 239000000120 Artificial Saliva Substances 0.000 description 3
- 239000005642 Oleic acid Substances 0.000 description 3
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 210000004211 gastric acid Anatomy 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 210000004379 membrane Anatomy 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 210000004400 mucous membrane Anatomy 0.000 description 3
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 3
- 239000006191 orally-disintegrating tablet Substances 0.000 description 3
- 150000003904 phospholipids Chemical class 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 2
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 2
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 2
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 239000011258 core-shell material Substances 0.000 description 2
- 238000005336 cracking Methods 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 239000003651 drinking water Substances 0.000 description 2
- 235000020188 drinking water Nutrition 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 150000004804 polysaccharides Polymers 0.000 description 2
- 230000001568 sexual effect Effects 0.000 description 2
- 235000019605 sweet taste sensations Nutrition 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 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 description 1
- 229920001503 Glucan Polymers 0.000 description 1
- 229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 210000005226 corpus cavernosum Anatomy 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
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- 230000012202 endocytosis Effects 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 235000009200 high fat diet Nutrition 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
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- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Classifications
-
- 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
- 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
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- 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
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
Abstract
The invention discloses a tadalafil freeze-drying flash-release tablet and a preparation process thereof, wherein the tadalafil freeze-drying flash-release tablet comprises the following components: 1-10 parts of tadalafil, 1-20 parts of a propping agent, 1-20 parts of a binder and 0.1-5 parts of a sweetening agent. Wherein, when the propping agent is mannitol and the adhesive is pullulan, the freeze-dried quick-release tablet has good forming and quick disintegration time, and the optimal addition amount of the mannitol and the pullulan is determined through experiments. The tadalafil freeze-dried flash-release tablet prepared by the invention has the advantages of good forming, rapid disintegration, improved bioavailability, convenience for patients to take medicine, rapid effect and reduced waiting time after taking medicine.
Description
Technical Field
The invention relates to the field of medicines, in particular to a tadalafil freeze-dried flash-release tablet and a preparation process thereof.
Background
Tadalafil (Tadalafil), chemically known as (6R-12aR) -6- (1, 3-benzodioxol-5-yl) -2-methyl-2, 3,6,7,12,12 a-hexahydropyrazino [1',2' -1,6] -pyrido [3,4-b ] indole-1, 4-dione, is a cyclic guanosine monophosphate (cGMP) specific phosphodiesterase 5(PDE5) inhibitor, and acts to treat male Erectile Dysfunction (ED) by increasing cGMP levels in the corpora cavernosa to relax smooth muscle, resulting in increased penile blood flow. Approved by the FDA in the united states for marketing in 2003 as a drug for the treatment of ED. Tadalafil has rapid onset of action and long duration of drug action, and is the only drug which is not influenced by high-fat diet and alcohol intake in the current four anti-ED drugs. Besides the ED indications, tadalafil was approved for Pulmonary Arterial Hypertension (PAH) and Benign Prostatic Hyperplasia (BPH) in turn.
Today, tadalafil tablets, i.e. formulations of celecoxib, are used clinically. It is taken orally at least 30 minutes before sexual life, and reaches the peak blood medicine concentration in 2 hours. The long waiting period after taking the medicine causes a certain stress to the psychology of the patient, and the quality of the sexual life is influenced. Some patients may not have drinking water around the patient when taking the tablet, which greatly limits the application range of the tablet, and the excessively obvious action of taking the medicine also puts certain stress on the psychology of the patient. In order to improve the performance of the medicine, facilitate the medicine taking of patients, simultaneously take effect quickly and reduce the waiting time after the medicine taking. At this time, the tadalafil freeze-dried flash-release tablet which is convenient to take and takes effect quickly has great research and development significance and market potential.
The flash release tablet is taken as a novel drug delivery system, has a plurality of remarkable characteristics, and is firstly directly put into the oral cavity without drinking water for taking, so that the tablet is convenient to take, has quick response, can be quickly dissolved in the oral cavity, releases the drug, can ensure that most of the drug is absorbed into blood circulation through oral mucosa, and has quick response.
Patent CN105611918B discloses an orally disintegrating film preparation containing tadalafil and a method for producing the same, which comprises tadalafil as an active ingredient; and a combination of pullulan and polyvinylpyrrolidone as a film forming agent. The orally disintegrating film formulation of the invention does not show oral absorption and can be formulated to show bioequivalence to a tablet containing tadalafil. And the orally disintegrating film formulation of the invention shows excellent stability. The preparation method has the problems that the tadalafil orally disintegrating film preparation prepared by the invention does not have oral absorption, so that the effect of the medicament is not fast enough, the first pass effect of the liver cannot be avoided, the utilization rate of the unit medicament is low, and adverse reactions are likely to occur.
Patent CN112972405A discloses a tadalafil freeze-dried orally disintegrating tablet and a preparation method thereof, the tadalafil freeze-dried orally disintegrating tablet prepared by the invention comprises tadalafil and pullulan, and the invention shows that although the freeze-dried orally disintegrating tablet can be prepared by using different thickeners, the effect is different in the actual use process, the prepared product has better appearance forming and quick response when being taken, has good compliance and improves the bioavailability. The invention has the problems that the pullulan has strong hydrophilicity, has no obvious synergistic effect on the direct absorption of tadalafil in a mucous membrane part, causes lower absorption amount through the mucous membrane, has unobvious improvement on the unit drug utilization rate, and needs to be further improved.
Disclosure of Invention
In view of the defects of slow effect and low bioavailability of tadalafil tablet medicaments in the prior art, the invention provides a tadalafil freeze-dried flash release tablet and a preparation process thereof.
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
a tadalafil freeze-dried flash-release tablet comprises the following components: tadalafil, proppant, binder, sweetener.
Preferably, the tadalafil freeze-dried flash-release tablet comprises the following components in parts by mass: 1-10 parts of tadalafil, 1-20 parts of a propping agent, 1-20 parts of a binder and 0.1-5 parts of a sweetening agent.
Preferably, the proppant is any one of mannitol, dextrin, starch and microcrystalline cellulose.
Further preferably, the proppant is mannitol.
Mannitol is a sugar alcohol, is an isomer of sorbitol, has sweet taste similar to sucrose, has no hygroscopicity, is dried quickly, has good chemical stability, and has the characteristics of good taste and granulation property. It absorbs heat when dissolved, has sweet taste and obvious comfort to the oral cavity, and mannitol can be absorbed by the intestines and stomach of human, but does not accumulate in the body, so that the mannitol has good biocompatibility, so the mannitol is preferably used as a propping agent of the flash release tablet.
Preferably, the binder is any one of pullulan, sodium carboxymethyl cellulose, hydroxypropyl cellulose and methyl cellulose.
Further preferably, the binder is pullulan.
The pullulan is a natural degradable macromolecular polymer, is extracellular water-soluble mucoid sugar which is produced by fermenting pullulan and is similar to glucan and xanthan gum, has no harm, is easy to prepare into a film and has good biocompatibility. Pullulan has many advantageous properties due to its specific polysaccharide structure. Pullulan, which contains 9 hydroxyl groups per glucose unit, is very soluble in water, is stable in aqueous solution, has a low viscosity compared to other water-soluble polysaccharides, and is not affected by temperature, pH, and most metal ions, and thus is frequently used as a food additive as well as a pharmaceutical additive.
And a great deal of experiments show that the forming rate and the disintegration speed of the flash-release tablet prepared by taking the pullulan as the binder are obviously improved by other binders, so that the pullulan is preferably taken as the binder to prepare the tadalafil freeze-dried flash-release tablet.
Preferably, the sweetener is any one of sucralose, aspartame, neotame, sucrose and acesulfame potassium.
The invention also provides a preparation method of the tadalafil freeze-dried flash-release tablet, which comprises the following steps:
s1, dissolving the adhesive in water to obtain an adhesive aqueous solution;
s2, adding the sweetener, the proppant and the tadalafil into the adhesive aqueous solution, dissolving, and adding water to a constant volume to obtain a feed liquid;
s3, emulsifying the feed liquid and degassing to obtain degassed feed liquid;
s4, respectively filling the degassed liquid into the bubble holes of the bubble cap plate to obtain the bubble cap plate filled with the liquid;
s5, pre-freezing the bubble cap plate filled with the feed liquid;
s6, freeze-drying the pre-frozen bubble-cap plate;
s7, packaging and cutting the freeze-dried bubble-cap plate.
Preferably, the emulsification condition in the step S3 is 5000-12000 rpm for 5-20 min.
Preferably, the pre-freezing method in the step S5 is to pre-freeze the bubble cap plate filled with the feed liquid in a liquid nitrogen tunnel at a temperature of between-100 and-85 ℃ for 10 to 20 min.
Preferably, the lyophilization conditions in step S6 are as follows: transferring the pre-frozen bubble plate into a freeze dryer, and operating the following freeze-drying curve: keeping the temperature of minus 35 to minus 25 ℃ for 60 to 90 min; keeping the temperature of minus 25 to minus 15 ℃ for 300 to 360 min; keeping the temperature of minus 20 to minus 10 ℃ for 120 to 150 min; keeping the temperature of-15 to-5 ℃ for 120 to 150 min; keeping the temperature of the mixture at minus 5 to 5 ℃ for 60 to 90 min; running for 30-60 min at the temperature of-5-25 ℃, and keeping for 180-240 min at the temperature of 25-30 ℃.
Preferably, the preparation method of the tadalafil freeze-dried flash-release tablet comprises the following steps:
s1, 100-300 mL of water is measured and placed in a beaker, the beaker is heated in a water bath at 50-65 ℃, 1-20 g of adhesive is weighed and added into the beaker, the mixture is stirred to be completely dissolved, and the mixture is cooled to 20-30 ℃ to obtain an adhesive aqueous solution;
s2, weighing 0.1-5 g of sweetening agent, 1-20 g of propping agent and 1-10 g of tadalafil, adding into the adhesive aqueous solution, stirring to completely dissolve, adding water and fixing the volume to 500mL to obtain feed liquid;
s3, emulsifying the feed liquid in an emulsifying machine at the rotating speed of 5000-12000 rpm for 5-20 min; vacuum degassing the emulsified feed liquid for 10-20 min to obtain degassed feed liquid;
s4, distributing the degassed liquid into bubble holes of a bubble cap plate according to 0.5-5 mL/sheet to obtain the bubble cap plate filled with the liquid;
s5, placing the bubble cap plate filled with the feed liquid into a liquid nitrogen tunnel at the temperature of-100 to-85 ℃ for pre-freezing for 10 to 20 min;
s6 the pre-frozen blister card was transferred to a lyophilizer and the following lyophilization profile was run: keeping the temperature of minus 35 to minus 25 ℃ for 60 to 90 min; keeping the temperature of minus 25 to minus 15 ℃ for 300 to 360 min; keeping the temperature of minus 20 to minus 10 ℃ for 120 to 150 min; keeping the temperature of-15 to-5 ℃ for 120 to 150 min; keeping the temperature of minus 5 to 5 ℃ for 60 to 90 min; running for 30-60 min at the temperature of-5-25 ℃, and keeping for 180-240 min at the temperature of 25-30 ℃;
s7, taking out the bubble-cap plate from the freeze dryer, and coating, packaging and cutting the bubble-cap plate on a sealing machine.
Compared with the prior art, the invention has the beneficial effects that:
1. the tadalafil freeze-dried flash-release tablet prepared by the method is good in forming, free of the phenomena of cracking and collapsing, and free of the phenomenon of shrinking after being placed under the condition of an accelerated test to prevent sampling for 2 months.
2. The tadalafil freeze-dried flash-release tablet prepared by the invention is quick to disintegrate, can improve the bioavailability of the medicament, is convenient for patients to take the medicament, and simultaneously takes effect quickly, and reduces the waiting time after the medicament is taken.
Detailed Description
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
The specific parameters of some substances and instruments in the examples of the invention are as follows:
tadalafil, Shandong Tetmann pharmaceutical Co., Ltd;
pullulan, jieyuqing jingmo (r), jieyu de ltd;
mannitol, Shandong Tianli pharmaceutical Co., Ltd;
artificial saliva, bioscience, ltd, shanghai yumu.
Example 1
A preparation method of tadalafil freeze-dried flash-release tablets comprises the following steps:
s1, measuring 300mL of water, putting the water into a beaker, heating the water in a water bath at 50 ℃, weighing 16.5g of pullulan, adding the pullulan into the beaker, stirring the pullulan to be completely dissolved, and cooling the pullulan to 25 ℃ to obtain a pullulan aqueous solution;
s2, weighing 0.9g of sucralose, 17.5g of mannitol and 10g of tadalafil, adding the sucralose, the mannitol and the tadalafil into the pullulan aqueous solution, stirring the mixture to be completely dissolved, and adding water to a constant volume of 500mL to obtain feed liquid;
s3 emulsifying the feed liquid in an emulsifying machine at 10000rpm for 10 min; vacuum degassing the emulsified feed liquid for 10min to obtain degassed feed liquid;
s4, respectively filling the degassed feed liquid into the bubble holes of the bubble cap plate according to 0.5 mL/piece to obtain the bubble cap plate filled with the feed liquid;
s5 placing the bubble cap plate filled with the feed liquid into a liquid nitrogen tunnel at the temperature of 100 ℃ below zero for pre-freezing for 10 min;
s6 the pre-frozen blister card was transferred to a lyophilizer and the following lyophilization profile was run: holding at-35 deg.C for 60 min; maintaining at-25 deg.C for 300 min; holding at-20 deg.C for 120 min; holding at-15 deg.C for 120 min; holding at-5 deg.C for 60 min; running at 15 deg.C for 30min, and maintaining at 25 deg.C for 180 min;
s7, taking out the bubble-cap plate from the freeze dryer, and coating, packaging and cutting the bubble-cap plate on a sealing machine.
Example 2
The preparation method of the tadalafil freeze-dried flash-release tablet has the same steps as the example 1, and is different from the production formula.
| Raw materials | Amount of use (g) |
| Tadalafil | 10.0 |
| Mannitol | 15.0 |
| Pullulan polysaccharide | 17.5 |
| Sucralose | 0.9 |
Example 3
The preparation method of the tadalafil freeze-dried flash-release tablet has the same steps as the example 1, and is different from the production formula.
Comparative example 1
The preparation method of the tadalafil freeze-dried flash-release tablet has the same steps as the example 1, and is different from the production formula.
| Raw materials | Amount of use (g) |
| Tadalafil | 10.0 |
| Mannitol | 12.5 |
| Pullulan polysaccharide | 15.0 |
| Sucralose | 0.9 |
Comparative example 2
The preparation method of the tadalafil freeze-dried flash-release tablet has the same steps as the example 1, and is different from the production formula.
| Raw materials | Amount of use (g) |
| Tadalafil | 10.0 |
| Mannitol | 10.0 |
| Pullulan polysaccharide | 12.5 |
| Sucralose | 0.9 |
Test example 1
And (3) testing the formation of the tadalafil freeze-dried flash-release tablet:
the purpose of the experiment is as follows: observation of the Effect of binder to proppant ratio on the moldability of lyophilized flash release tablets
The experimental method comprises the following steps: after the sample is taken out of the box, observing whether the sample is cracked and collapsed by naked eyes; the plate was placed in a stability testing box under accelerated conditions (25 ℃ C., RH 60%) to observe whether the plate was shrunk or not.
The results of the experiment are shown in table 1:
TABLE 1 Tadalafil lyophilized flash-release tablet formation test results
From the results in table 1, it is found that the ratio (g/mL,%) of pullulan in the feed liquid is 3.3 to 3.7%; the content of mannitol in the feed liquid (g/mL,%) is 2.8-3.5%, the obtained freeze-dried flash-release tablet has good molding performance and no cracking and collapse phenomena, and the sample is placed for about 2 months under the condition of placing accelerated test, and the sample in the example has no shrinkage phenomenon.
Test example 2
Oral disintegration time limit test of tadalafil freeze-dried flash release tablets:
the purpose of the experiment is as follows: the influence of different stabilizers and proppant ratios on the disintegration time of tadalafil freeze-dried flash-release tablets.
The experimental method comprises the following steps: the disintegrating basket is fixed on a bracket and is immersed into a 1000ml cup, about 900ml of water with the temperature of 37 +/-1 ℃ is contained in the cup, and the bottom of the basket is 15 +/-1 mm below the water surface. Sample 1 tablet was placed in a disintegration basket and the time to complete disintegration and passage through a 710 μm mesh was recorded.
The results of the experiment are shown in table 2:
TABLE 2 oral disintegration time limit test results for tadalafil lyophilized flash release tablets
| Sample (I) | Disintegration time limit(s) |
| Example 1 | 3 |
| Example 2 | 2 |
| Example 3 | 5 |
| Comparative example 1 | 3 (lobe) |
| Comparative example 2 | Collapse failure to determine |
The results in Table 2 show that the ratio (g/mL,%) of pullulan in the feed liquid in the examples is 3.3-3.7%; the content of mannitol in the feed liquid is 2.8-3.5%, and the obtained freeze-dried flash-release tablet disintegrates rapidly.
Example 4
A preparation method of tadalafil freeze-dried flash-release tablets comprises the following steps:
s1, measuring 300mL of water, placing the water in a beaker, heating the water in a water bath at 50 ℃, weighing 17.5g of modified pullulan, adding the modified pullulan into the beaker, stirring the mixture to completely dissolve the pullulan, and cooling the mixture to 25 ℃ to obtain a modified pullulan aqueous solution;
s2, 0.9g of sucralose, 15g of mannitol and 10g of tadalafil are weighed and added into the modified pullulan aqueous solution, and after the components are completely dissolved by stirring, water is added to the solution until the volume is up to 500mL to obtain feed liquid;
s3 emulsifying the feed liquid in an emulsifying machine at 10000rpm for 10 min; vacuum degassing the emulsified feed liquid for 10min to obtain degassed feed liquid;
s4, respectively filling the degassed feed liquid into the bubble holes of the bubble cap plate according to 0.5 mL/piece to obtain the bubble cap plate filled with the feed liquid;
s5 placing the bubble cap plate filled with the feed liquid into a liquid nitrogen tunnel at the temperature of 100 ℃ below zero for pre-freezing for 10 min;
s6 the pre-frozen blister card was transferred to a lyophilizer and the following lyophilization curve was run: holding at-35 deg.C for 60 min; holding at-25 deg.C for 300 min; holding at-20 deg.C for 120 min; holding at-15 deg.C for 120 min; holding at-5 deg.C for 60 min; running at 15 deg.C for 30min, and maintaining at 25 deg.C for 180 min;
s7, taking out the bubble-cap plate from the freeze dryer, and coating, packaging and cutting the bubble-cap plate on a sealing machine.
The preparation method of the modified pullulan comprises the following steps: dissolving 0.85g of oleic acid, 0.56g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide and 0.37g of 4-dimethylaminopyridine in 10mL of dimethyl sulfoxide, stirring and activating for 1h at 25 ℃, adding the activated reaction solution into 10mL of 18 wt% pullulan polysaccharide dimethyl sulfoxide solution, stirring and reacting for 48h at 25 ℃, after the reaction is finished, adding the reaction solution into 500mL of ethanol, filtering and collecting white precipitate, washing the precipitate for 3 times with ethanol, dissolving the precipitate in 15mL of water, transferring the precipitate into a dialysis bag with the molecular weight cutoff of 10000, dialyzing for 3d in water, and freeze-drying for 48h at-45 ℃ after the dialysis is finished to obtain the modified pullulan polysaccharide.
The tadalafil belongs to BCS IV class medicines, the medicines are poor in solubility and poor in bioavailability, after the quick-release tablets are quickly dispersed and dissolved in the oral cavity, the medicines are distributed in the oral cavity in a large area and have multiple absorption points, wherein one part of the medicines are absorbed by capillary vessels such as buccal parts and sublingual parts, oral cavities, pharyngeal parts and mucous membranes of esophagus, so that part of the medicines directly reach systemic circulation through superior vena cava before reaching the stomach, thereby reducing the local stimulation of the tadalafil to gastrointestinal tracts, reducing the intestinal residue, relieving the side effect of the intestines and stomach, shortening the onset time and reducing the first pass effect and the gastric acid degradation effect of the liver. Therefore, in order to improve the bioavailability thereof, it is required to improve the absorption efficiency of tadalafil on the mucosa.
The pullulan is a natural degradable macromolecular polymer, has no harm, is easy to prepare into a film, has good biocompatibility, is paid much attention to in the medical field due to a large number of excellent characteristics, and has certain limitation in application. The pullulan has no electronegativity and strong hydrophilicity, so that the permeation flux of the drug on mucosa is small, and the drug availability is reduced due to the first pass effect.
In order to solve the problem, in the embodiment, the pullulan is modified, and because the pullulan has a large number of hydroxyl groups, oleic acid with hydrophobicity is connected to the main chain of the pullulan through an esterification reaction, so that the modified pullulan has amphipathy, the mucoadhesion effect of the drug is improved, and the mucosal absorption time is prolonged. And due to the lipid composition of the mucosal epithelium, the distribution phenomenon entering the epithelium causes the main factor for driving the absorption of tadalafil, and the modified pullulan polysaccharide can build different chemical interactions with membrane phospholipid to increase the permeability of epithelial cells, thereby being beneficial to the permeation and absorption of tadalafil. Therefore, the modified pullulan polysaccharide can remarkably improve the permeation flux of tadalafil on mucosa and improve the drug availability by prolonging the mucosal absorption time and improving the permeability of mucosal epithelial cells.
Example 5
A preparation method of tadalafil freeze-dried flash-release tablets comprises the following steps:
s1, measuring 300mL of water, placing the water in a beaker, heating the water in a water bath at 50 ℃, weighing 17.5g of pullulan, adding the pullulan into the beaker, stirring the pullulan to be completely dissolved, and cooling the solution to 25 ℃ to obtain a pullulan aqueous solution;
s2, 0.9g of sucralose, 15g of mannitol, 10g of tadalafil and 10g of tween 80 are weighed and added into the pullulan aqueous solution, and after the materials are completely dissolved by stirring, water is added to the solution until the volume is up to 500mL, so that feed liquid is obtained;
s3 emulsifying the feed liquid in an emulsifying machine at 10000rpm for 10 min; vacuum degassing the emulsified feed liquid for 10min to obtain degassed feed liquid;
s4, respectively filling the degassed feed liquid into the bubble holes of the bubble cap plate according to 0.5 mL/piece to obtain the bubble cap plate filled with the feed liquid;
s5 placing the bubble cap plate filled with the feed liquid into a liquid nitrogen tunnel at the temperature of 100 ℃ below zero for pre-freezing for 10 min;
s6 the pre-frozen blister card was transferred to a lyophilizer and the following lyophilization profile was run: holding at-35 deg.C for 60 min; holding at-25 deg.C for 300 min; holding at-20 deg.C for 120 min; holding at-15 deg.C for 120 min; holding at-5 deg.C for 60 min; running at 15 deg.C for 30min, and maintaining at 25 deg.C for 180 min;
s7 taking out the blister plate from the freeze dryer, coating and packaging on a sealing machine, and cutting.
Example 6
A preparation method of tadalafil freeze-dried flash-release tablets comprises the following steps:
s1, measuring 300mL of water, placing the water in a beaker, heating the water in a water bath at 50 ℃, weighing 17.5g of modified pullulan, adding the modified pullulan into the beaker, stirring the mixture to completely dissolve the pullulan, and cooling the mixture to 25 ℃ to obtain a modified pullulan aqueous solution;
s2, 0.9g of sucralose, 15g of mannitol, 10g of tadalafil and 10g of tween 80 are weighed and added into the modified pullulan aqueous solution, and after the materials are completely dissolved by stirring, water is added to the solution until the volume is up to 500mL, so that feed liquid is obtained;
s3 emulsifying the feed liquid in an emulsifying machine at 10000rpm for 10 min; vacuum degassing the emulsified feed liquid for 10min to obtain degassed feed liquid;
s4, respectively filling the degassed feed liquid into the bubble holes of the bubble cap plate according to 0.5 mL/piece to obtain the bubble cap plate filled with the feed liquid;
s5 placing the bubble cap plate filled with the feed liquid into a liquid nitrogen tunnel at the temperature of 100 ℃ below zero for pre-freezing for 10 min;
s6 the pre-frozen blister card was transferred to a lyophilizer and the following lyophilization curve was run: holding at-35 deg.C for 60 min; holding at-25 deg.C for 300 min; holding at-20 deg.C for 120 min; holding at-15 deg.C for 120 min; holding at-5 deg.C for 60 min; running at 15 deg.C for 30min, and maintaining at 25 deg.C for 180 min;
s7, taking out the bubble-cap plate from the freeze dryer, and coating, packaging and cutting the bubble-cap plate on a sealing machine.
The preparation method of the modified pullulan comprises the following steps: dissolving 0.85g of oleic acid, 0.56g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide and 0.37g of 4-dimethylaminopyridine in 10mL of dimethyl sulfoxide, stirring and activating for 1h at 25 ℃, adding the activated reaction solution into 10mL of 18 wt% pullulan polysaccharide dimethyl sulfoxide solution, stirring and reacting for 48h at 25 ℃, after the reaction is finished, adding the reaction solution into 500mL of ethanol, filtering and collecting white precipitate, washing the precipitate for 3 times with ethanol, dissolving the precipitate in 15mL of water, transferring the precipitate into a dialysis bag with the molecular weight cutoff of 10000, dialyzing for 3d in water, and freeze-drying for 48h at-45 ℃ after the dialysis is finished to obtain the modified pullulan polysaccharide.
In subsequent experiments, the improvement of the permeation flux of tadalafil on mucosa is not obvious by using the flash-release tablet prepared from the modified pullulan, and then analysis shows that the possible reason is that the modified pullulan can be automatically assembled in an aqueous solution to form a nano micelle with a unique core-shell structure, the hydrophobic segment wraps tadalafil in a hydrophobic core through hydrophobic interaction, and a hydrophilic polysaccharide chain forms a shell structure, although the drug-carrying micelle stabilizes a carrier structure, improves certain drug availability, and simultaneously reduces the toxic and side effects of the drug on an organism, the micelle structure also avoids the first pass effect and the gastric acid degradation effect of the drug to a certain extent, but the effect of free modified pullulan on mucosa is reduced due to the micelle formation of a large amount of the modified pullulan, so that the absorption efficiency of tadalafil on mucosa is lowered, the onset of action is increased.
In order to solve the problem, on the premise of using the modified pullulan, the surfactant Tween 80 is added, the mucoadhesion effect can be obviously improved by the synergistic effect of the modified pullulan and the Tween 80, and the permeability of epithelial cells can be further increased by establishing different chemical interactions with membrane phospholipid through the combination of the modified pullulan and the Tween 80, so that the permeation and the absorption of tadalafil are facilitated. In addition, under the action of Tween 80, the permeability of epithelial cells is increased, and the micelles wrapping tadalafil can also be absorbed and utilized by a human body in an endocytosis mode, so that the absorption efficiency and the bioavailability are further improved.
Test example 3
Epithelial cell in vitro penetration test: the excised epithelium of pig feeding tube was used as a barrier to drug permeation, and the radius of the feeding chamber was 0.9cm, and the permeation area was about 2.54cm2The receiving and supply chambers had a volume of about 8 mL. During testing, the pig feeding tube epithelium is placed between two chambers of the diffusion pool, and the pig feeding tube epithelium is held in close contact with the receiving liquid and the supply liquid. Wherein the supply solution is 1 tadalafil lyophilized flash release tablet prepared in examples 2 and 4-6 respectively dissolved in 8mL of artificial saliva, and the receiving solution is 8mL of artificial saliva. Stirring the device in a 37 deg.C constant temperature water bath at 300rpm for 24h, terminating the test, and detecting the content of tadalafil in the receiving solution by high performance liquid chromatography, the results are shown in Table 3Shown in the figure.
TABLE 3 epithelial cell in vitro permeation test results
| Content (mg) of tadalafil in the receiving liquid | |
| Example 2 | 0.26 |
| Example 4 | 1.37 |
| Example 5 | 1.98 |
| Example 6 | 3.86 |
Through a drug transepithelial cell test, the permeation flux of the tadalafil freeze-dried flash-release tablet prepared in the embodiment on a mucosa can be obtained by comparing the content of tadalafil in a receiving liquid, and the larger the content of tadalafil in the receiving liquid is, the larger the permeation flux of the tadalafil freeze-dried flash-release tablet on the mucosa is, which means that the more the amount of tadalafil absorbed through the mucosa is, the more the drug can avoid the first pass effect and the gastric acid degradation effect, so that the higher the drug availability of tadalafil is.
As can be seen from the results in table 3, the permeation flux of the tadalafil lyophilized flash release tablet prepared in example 6 was the largest on the mucosa, and the permeation flux of the tadalafil lyophilized flash release tablet prepared in example 2 was the smallest on the mucosa. The possible reasons for this are that pullulan has no electronegativity, is strongly hydrophilic, and has no interaction between epithelial cells, whereas absorption of tadalafil by epithelial cells is mainly through a form of passive diffusion, and thus the permeation flux on mucosa is low for example 2; both the modified pullulan and tween 80 have amphiphilicity, and can remarkably improve the permeation flux of tadalafil on the mucosa by prolonging the mucosal absorption time and improving the permeability of mucosal epithelial cells, so that examples 4 and 5 have remarkable improvement in the permeation flux on the mucosa compared with example 2, and the modified pullulan can be self-assembled in an aqueous solution to form nano-micelles with unique core-shell structures, resulting in less free modified pullulan, so that the permeation flux on the mucosa of example 5 is better than that of example 4; in example 6, free modified pullulan and tween 80 significantly improved mucoadhesion through synergistic effects and further increased permeability of epithelial cells by establishing different chemical interactions with membrane phospholipids.
Claims (10)
1. The tadalafil freeze-dried flash-release tablet is characterized by comprising the following components: tadalafil, proppant, binder, sweetener.
2. The tadalafil freeze-dried flash release tablet according to claim 1, comprising the following components in parts by mass: 1-10 parts of tadalafil, 1-20 parts of a propping agent, 1-20 parts of a binder and 0.1-5 parts of a sweetening agent.
3. The tadalafil lyophilized flash release tablet of claim 1 or 2, wherein: the proppant is any one of mannitol, dextrin, starch and microcrystalline cellulose.
4. The tadalafil lyophilized flash release tablet of claim 3, wherein: the proppant is mannitol.
5. The tadalafil lyophilized flash release tablet of claim 1 or 2, wherein: the adhesive is any one of pullulan polysaccharide, sodium carboxymethyl cellulose, hydroxypropyl cellulose and methyl cellulose.
6. The tadalafil lyophilized flash release tablet of claim 5, wherein: the adhesive is pullulan.
7. The tadalafil lyophilized flash release tablet of claim 1 or 2, wherein: the sweetener is any one of sucralose, aspartame, neotame, sucrose and acesulfame potassium.
8. The method for preparing tadalafil freeze-dried flash release tablets according to any of the claims 1 to 7, comprising the steps of:
s1, dissolving the adhesive in water to obtain an adhesive aqueous solution;
s2, adding the sweetener, the proppant and the tadalafil into the adhesive aqueous solution, dissolving, and adding water to a constant volume to obtain a feed liquid;
s3, emulsifying the feed liquid and degassing to obtain degassed feed liquid;
s4, respectively filling the degassed liquid into the bubble holes of the bubble cap plate to obtain the bubble cap plate filled with the liquid;
s5, pre-freezing the bubble cap plate filled with the feed liquid;
s6, freeze-drying the pre-frozen bubble-cap plate;
s7, packaging and cutting the freeze-dried bubble-cap plate.
9. The method for preparing tadalafil lyophilized flash tablets according to claim 8, wherein: the emulsification condition in the step S3 is that the rotation speed is 5000-12000 rpm and the emulsification is carried out for 5-20 min.
10. The method for preparing tadalafil lyophilized flash release tablet according to claim 8, wherein the lyophilization conditions in step S6 are: transferring the pre-frozen bubble plate into a freeze dryer, and operating the following freeze-drying curve: keeping the temperature of minus 35 to minus 25 ℃ for 60 to 90 min; keeping the temperature of minus 25 to minus 15 ℃ for 300 to 360 min; keeping the temperature of minus 20 to minus 10 ℃ for 120 to 150 min; keeping the temperature of-15 to-5 ℃ for 120 to 150 min; keeping the temperature of the mixture at minus 5 to 5 ℃ for 60 to 90 min; running for 30-60 min at the temperature of-5-25 ℃, and keeping for 180-240 min at the temperature of 25-30 ℃.
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| CN114652689B (en) | 2023-04-07 |
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Effective date of registration: 20230724 Address after: Building 3, No. 12, Wuchu Avenue, Fankou Street, Echeng District, Ezhou, Hubei Province, 436000 Patentee after: Hubei Feirui Biopharmaceutical Co.,Ltd. Address before: 061000 exhibition culture industrial park, Cangzhou Economic Development Zone, Jiefang East Road, Cangzhou Economic Development Zone, Hebei Province Patentee before: Hebei Feirui Biotechnology Co.,Ltd. |