CN111084777A - Piribedil, levodopa and benserazide compound sustained-release three-layer tablet and preparation method thereof - Google Patents
Piribedil, levodopa and benserazide compound sustained-release three-layer tablet and preparation method thereof Download PDFInfo
- Publication number
- CN111084777A CN111084777A CN202010087042.9A CN202010087042A CN111084777A CN 111084777 A CN111084777 A CN 111084777A CN 202010087042 A CN202010087042 A CN 202010087042A CN 111084777 A CN111084777 A CN 111084777A
- Authority
- CN
- China
- Prior art keywords
- layer
- release
- levodopa
- benserazide
- 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
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 title claims abstract description 70
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 title claims abstract description 69
- 229960004502 levodopa Drugs 0.000 title claims abstract description 65
- OQDPVLVUJFGPGQ-UHFFFAOYSA-N 2-[4-(1,3-benzodioxol-5-ylmethyl)-1-piperazinyl]pyrimidine Chemical compound C=1C=C2OCOC2=CC=1CN(CC1)CCN1C1=NC=CC=N1 OQDPVLVUJFGPGQ-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 229960004310 piribedil Drugs 0.000 title claims abstract description 51
- 229960000911 benserazide Drugs 0.000 title claims abstract description 43
- -1 benserazide compound Chemical class 0.000 title claims abstract description 23
- 238000013268 sustained release Methods 0.000 title claims abstract description 23
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title abstract description 25
- 239000011248 coating agent Substances 0.000 claims abstract description 34
- 238000000576 coating method Methods 0.000 claims abstract description 34
- 239000012528 membrane Substances 0.000 claims abstract description 15
- 238000004080 punching Methods 0.000 claims abstract description 13
- 239000004480 active ingredient Substances 0.000 claims abstract description 11
- 238000007908 dry granulation Methods 0.000 claims abstract description 11
- 238000005550 wet granulation Methods 0.000 claims abstract description 6
- 239000003826 tablet Substances 0.000 claims description 62
- 239000003814 drug Substances 0.000 claims description 50
- BNQDCRGUHNALGH-UHFFFAOYSA-N benserazide Chemical compound OCC(N)C(=O)NNCC1=CC=C(O)C(O)=C1O BNQDCRGUHNALGH-UHFFFAOYSA-N 0.000 claims description 36
- 238000002156 mixing Methods 0.000 claims description 31
- 229940079593 drug Drugs 0.000 claims description 29
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 26
- 239000008187 granular material Substances 0.000 claims description 25
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 14
- 235000019359 magnesium stearate Nutrition 0.000 claims description 13
- 238000002955 isolation Methods 0.000 claims description 10
- 229960001335 benserazide hydrochloride Drugs 0.000 claims description 9
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 8
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 8
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 8
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 7
- 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 7
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims description 7
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 claims description 7
- 239000011780 sodium chloride Substances 0.000 claims description 7
- 239000000853 adhesive Substances 0.000 claims description 6
- 230000001070 adhesive effect Effects 0.000 claims description 6
- 230000032683 aging Effects 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 239000000945 filler Substances 0.000 claims description 6
- 239000000314 lubricant Substances 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- 238000003825 pressing Methods 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 5
- 239000007939 sustained release tablet Substances 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 229920002301 cellulose acetate Polymers 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000002245 particle Substances 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 239000003381 stabilizer Substances 0.000 claims description 3
- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- 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 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- 230000002496 gastric effect Effects 0.000 claims description 2
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims 1
- 229960003943 hypromellose Drugs 0.000 claims 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 claims 1
- 230000003204 osmotic effect Effects 0.000 claims 1
- 239000003405 delayed action preparation Substances 0.000 abstract description 2
- 239000010410 layer Substances 0.000 description 70
- 230000000052 comparative effect Effects 0.000 description 19
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 16
- 208000018737 Parkinson disease Diseases 0.000 description 11
- 210000004556 brain Anatomy 0.000 description 10
- 238000004090 dissolution Methods 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 8
- 229960003638 dopamine Drugs 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 150000003943 catecholamines Chemical class 0.000 description 7
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 5
- 102100038238 Aromatic-L-amino-acid decarboxylase Human genes 0.000 description 4
- 108010035075 Tyrosine decarboxylase Proteins 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 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 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 description 3
- 229960001681 croscarmellose sodium Drugs 0.000 description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 3
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 3
- 239000007888 film coating Substances 0.000 description 3
- 238000009501 film coating Methods 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 230000002093 peripheral effect Effects 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229940068968 polysorbate 80 Drugs 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 230000000648 anti-parkinson Effects 0.000 description 2
- 239000000939 antiparkinson agent Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000008499 blood brain barrier function Effects 0.000 description 2
- 210000001218 blood-brain barrier Anatomy 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 230000004087 circulation Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 229940052760 dopamine agonists Drugs 0.000 description 2
- 230000003291 dopaminomimetic effect Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 description 1
- 102000003823 Aromatic-L-amino-acid decarboxylases Human genes 0.000 description 1
- 108090000121 Aromatic-L-amino-acid decarboxylases Proteins 0.000 description 1
- 102000004031 Carboxy-Lyases Human genes 0.000 description 1
- 108090000489 Carboxy-Lyases Proteins 0.000 description 1
- 101150049660 DRD2 gene Proteins 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 208000002740 Muscle Rigidity Diseases 0.000 description 1
- 208000027089 Parkinsonian disease Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 206010039424 Salivary hypersecretion Diseases 0.000 description 1
- 208000008630 Sialorrhea Diseases 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- CJCSPKMFHVPWAR-JTQLQIEISA-N alpha-methyl-L-dopa Chemical compound OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 CJCSPKMFHVPWAR-JTQLQIEISA-N 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 229940035678 anti-parkinson drug Drugs 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- ULFCBIUXQQYDEI-UHFFFAOYSA-N benserazide hydrochloride Chemical compound Cl.OCC(N)C(=O)NNCC1=CC=C(O)C(O)=C1O ULFCBIUXQQYDEI-UHFFFAOYSA-N 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000005098 blood-cerebrospinal fluid barrier Anatomy 0.000 description 1
- 229960003563 calcium carbonate Drugs 0.000 description 1
- 229960004205 carbidopa Drugs 0.000 description 1
- TZFNLOMSOLWIDK-JTQLQIEISA-N carbidopa (anhydrous) Chemical compound NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 TZFNLOMSOLWIDK-JTQLQIEISA-N 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 239000003954 decarboxylase inhibitor Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- RZRNAYUHWVFMIP-HXUWFJFHSA-N glycerol monolinoleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-HXUWFJFHSA-N 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000003836 peripheral circulation Effects 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 210000003523 substantia nigra Anatomy 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 229960004441 tyrosine Drugs 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K9/2072—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
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Psychology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a piribedil, levodopa and benserazide compound sustained-release three-layer tablet and a preparation method thereof. The preparation process comprises the steps of wet granulation of the first tablet layer, dry granulation of the second tablet layer and the third tablet layer, tabletting by a three-layer tablet press, coating the sustained-release semipermeable membrane, and coating the rapid-release coating membrane after punching. The invention can prepare the piribedil, levodopa and benserazide compound sustained release preparation, realizes the feasibility of simultaneous administration, can ensure the stability of each active ingredient, and simultaneously ensures the stable release of the active ingredients.
Description
Technical Field
The invention belongs to the technical field of medicinal preparations, and particularly relates to a piribedil, levodopa and benserazide compound sustained-release three-layer tablet and a preparation method thereof.
Background
Piribedil is a dopaminergic agonist that stimulates the postsynaptic D2 receptor of the substantia nigra striatum of the brain and the D2 and D3 receptors of the mesolimbic pathway of the brain, providing potent dopamine effects. Clinical pharmacology studies have established the mechanism of action: 1. stimulating dopaminergic cortical angiogenesis in both awake and sleep states. 2. Different clinical functions under dopamine control have been demonstrated by tests on behavioral or psychometric scales. Furthermore, piribedil increases femoral artery blood flow (the presence of dopaminergic receptors in the femoral vascular bed explains the effect of piribedil on the peripheral circulation). For the treatment of parkinson's disease: can be used as single medicine, especially for treating patients with tremor as main symptom. Can also be used in combination with levodopa as an initial or late treatment.
Structural formula (xvi):
chemical name: [ (methylenedioxy-3, 4-benzyl) -4-piperazinyl-1 ] -2-pyrimidine
The molecular formula is as follows: c16H18N4O2
Molecular weight: 298.3
The L-dopa absorbed into blood is decarboxylated by about 95% of dopa decarboxylase in peripheral tissues to form catecholamine, which is not easy to pass through a blood brain barrier and causes a lot of adverse reactions, only 1% of L-dopa enters brain circulation and reaches the central nervous system to play a therapeutic role in transforming into the catecholamine, and the L-dopa does not have a remarkable pharmacological effect but indirectly plays a therapeutic role in playing a therapeutic role through the catecholamine.
Structural formula (xvi):
chemical name: 3-hydroxy-L-tyrosine.
The molecular formula is as follows: c9H11NO4
Molecular weight: 197.19
Specific optical rotation: -11.7(c ═ 5.3,1N HCl)
Melting point: 295 deg.C
Benserazide hydrochloride is a peripheral decarboxylase inhibitor and is combined with levodopa to prepare a compound preparation of the benserazide hydrochloride. Levodopa is an effective drug for treating Parkinson's disease, and the pharmacological action of levodopa is realized by converting levodopa into dopamine through decarboxylase action in the brain, and the dopamine in the brain can improve Parkinson's disease. However, most of levodopa is converted into dopamine by the action of aromatic Amino Acid Decarboxylase (AADC) in the week of external chemical book, only a small amount of levodopa can enter the brain, and the benserazide hydrochloride used as an AADC inhibitor and the levodopa are used together, so that the levodopa can be inhibited from being converted into dopamine outside the brain, the amount of the levodopa entering the brain is increased, and the symptoms of the Parkinson's disease are effectively improved.
Chemical name: 2-amino-3-hydroxy-N' - (2,3, 4-trihydroxybenzyl) propionylhydrazine hydrochloride
The molecular formula is as follows: c10H16ClN3O5
Molecular weight: 293.7
Melting point: 146 deg.C
Levodopa has been widely used in clinical practice in various countries in the world since 1908 years, and is currently the most effective drug for treating paralysis agitans. Levodopa has therapeutic effect on rigidity, dyskinesia, sialorrhea, and arterial crisis. Although levodopa is a good drug for the treatment of parkinson's disease, many physicians currently choose other drugs such as dopamine receptor agonists as treatment preferences as their best option without dopamine treatment in the first-onset patients due to its diminished efficacy and severe adverse effects. The drug forms a catecholamine intermediate, a dopamine precursor, from tyrosine. About 95% of the L-dopa absorbed into the blood is decarboxylated by dopa decarboxylase in peripheral tissues to form catecholamine, which is not easy to pass through the blood brain barrier and causes many adverse reactions. Only 1% of L-dopa enters the brain circulation and reaches the central nervous system, where it is converted into catecholamine for therapeutic effect. It has no obvious pharmacological action, but indirectly exerts curative effect through catecholamine. DDC inhibitors such as carbidopa, benserazide, etc. are often co-administered in order to reduce the peripheral conversion of levodopa. DDC inhibitors do not readily cross the blood-cerebrospinal fluid barrier by themselves, but increase the amount of levodopa entering the brain by reducing levodopa degradation at the periphery. The poly-barusine hydrazine is a compound preparation of levodopa and benserazide, has higher bioavailability, and is a leading variety in the world anti-Parkinson disease medicine market. Developed by roche swiss, 1973, and approved by the FDA under the trade name Madopar (medoba). Medobo is the main product in the domestic anti-parkinsonian drug market.
The piribedil is used as a dopaminergic agonist, belongs to a relatively important class of medicines in the drug market of anti-Parkinson's disease, is usually used for initial treatment, has a single use curative effect which is not as remarkable as that of levodopa, and is used as an auxiliary therapeutic agent when the curative effect of the levodopa is insufficient so as to reduce the influence of high-dose levodopa on neurons of the levodopa. Therefore, the piribedil is usually combined with the baysizid, and has obvious curative effect on treating the Parkinson's disease.
The existing marketed drugs are piribedil sustained-release tablets and levodopa and benserazide compound preparations such as polydibazazine, and the piribedil, levodopa and benserazide compound preparations which are convenient for patients to take are not available. The applicant finds that the mutual influence of the effective components exists when the piribedil, the levodopa and the benserazide are mixed and stored, the effective components are obviously reduced in the process of medicament storage, the impurity content is obviously increased, and the effective components in the compound preparation are difficult to release in a long-acting manner, so that the invention of the piribedil, the levodopa and the benserazide compound preparation which ensures the long-acting release of the medicament and has stable properties is urgently needed.
Disclosure of Invention
The invention aims to prepare a piribedil, levodopa and benserazide compound preparation. Overcomes the defect that the piribedil, the levodopa and the benserazide influence each other, ensures the long-acting release of the medicament, is convenient for taking the compound preparation, improves the compliance of patients, and provides a preparation method of the compound preparation.
According to the process of the multi-bushizine compound preparation, the piribedil, the levodopa and the benserazide are mixed to prepare the compound preparation, the auxiliary materials and the active ingredients are mutually influenced, impurities exceed the standard, the active ingredients of the medicine are quickly degraded, and the safety and the effectiveness of the medicine can not be ensured.
In order to avoid drug interaction, the invention carries out layered tabletting on the piribedil, the levodopa and the benserazide so as to ensure the stability of the drug. The medicine layering tabletting can avoid the interaction of effective components to a certain extent, but the contact part of the lamellar surface still can generate the interaction, and the long-term stability of the medicine can not be ensured. Therefore, the isolation layer is added between the two layers, so that the stability of each effective component can be effectively isolated, and the isolation layer can be used as a boosting layer to ensure the long-acting release of the medicament. The auxiliary materials selected by the isolation layer are compatible with active ingredients of the piribedil, the levodopa and the benserazide, the stability of the medicament is not influenced, and the isolation layer needs to have water absorbability and expansibility, so that the isolation layer plays a role of a boosting layer after entering a body and ensures long-acting stable release of the medicament. The slow release tablet needs to be perforated on two sides, because the slow release tablet is a three-layer tablet, the middle layer is an isolation boosting layer, the first layer and the third layer are medicine-containing layers, and the effective components of the last layer and the third layer entering the body are respectively released from the upper surface and the lower surface of the tablet so as to achieve the purpose of drug combination.
Specifically, the purpose of the invention is realized by the following scheme:
the invention relates to a three-layer sustained-release tablet which consists of a tablet core, a sustained-release layer and a film coating layer. The slow release layer and the film coating layer are sequentially coated on the surface of the tablet core, the weight of the film coating layer is increased by 1-3%, the weight of the slow release layer is increased to 6-12% of the weight of the tablet core, and the three-layer tablet core is sequentially a first layer, a second layer and a third layer. The active ingredient of the first tablet layer is piribedil, and also comprises pharmaceutic adjuvants such as a filler, a lubricant, a disintegrating agent, a solubilizer, a stabilizer, an adhesive and the like; the second sheet layer is an isolating layer and also serves as a boosting layer for sustained-release, the sheet layer is mainly used for isolating piribedil, levodopa and benserazide, mutual influence between active ingredients and auxiliary materials is avoided, the stability of the medicine is ensured, the main ingredients of the sheet layer are ethyl cellulose, glycerol monooleate, hydroxypropyl methylcellulose, magnesium stearate and red ferric oxide, the mixture absorbs water and expands through the sustained-release layer after entering the body, and the medicine containing layers on two sides are extruded to be dissolved and released; the third layer contains levodopa and benserazide or pharmaceutically acceptable salt thereof as active ingredients, and also contains pharmaceutical adjuvants such as filler, disintegrant, lubricant, etc.
Preferably, the content of the piribedil in the first layer of each tablet is 30-70 mg, and more preferably 50 mg.
Preferably, the levodopa content in the third layer of each tablet is 150-250 mg, and more preferably 200 mg; the content of benserazide or a pharmaceutically acceptable salt thereof is 25 to 80mg, and preferably 50mg in terms of benserazide.
Preferably, each tablet contains piribedil, levodopa, benserazide or a pharmaceutically acceptable salt thereof in a mass ratio of 50: 200: 50, wherein benserazide or a pharmaceutically acceptable salt thereof is calculated as benserazide.
Preferably, the first sheet layer comprises the following components by mass:
preferably, the second sheet layer comprises the following components by mass:
preferably, the third sheet layer comprises the following components by mass:
the coating film comprises the following components in percentage by mass:
slow release semipermeable membranes: 28-70 parts of cellulose acetate
2-6 parts of polyethylene glycol
Quick-release coating film: 5-20 parts of gastric soluble coating powder
The preparation method of the tablet comprises the following steps:
(1) uniformly mixing the piribedil bulk drug, the first tablet disintegrating agent, the filler and the stabilizer in a formula ratio in a mixer, adding the prepared binder solution containing the solubilizer, performing wet granulation, drying and finishing wet granules, adding the lubricant, and uniformly mixing to obtain uniformly mixed first tablet granules;
(2) uniformly mixing the second lamellar polyoxyethylene, sodium chloride, red ferric oxide and hydroxypropyl methylcellulose in a formula ratio in a mixer, performing dry granulation, adding magnesium stearate, and uniformly mixing to obtain second lamellar granules;
(3) uniformly mixing the levodopa bulk drug and the benserazide hydrochloride bulk drug with the third-layer disintegrating agent, the filling agent and the adhesive in a formula ratio in a mixer, performing dry granulation, adding the lubricant, and uniformly mixing to obtain third-layer particles;
(4) adding the obtained granules into corresponding slice layer charging hoppers respectively, and pressing into a three-layer slice to obtain a tablet core;
(5) coating a slow-release semipermeable membrane on a tablet core, aging properly, and punching holes on the upper surface and the lower surface of the tablet core by using a laser punching machine;
(6) finally, the coating is coated with a quick-release coating film.
Compared with the prior art, the invention has the following beneficial effects:
the invention aims to prepare a piribedil, levodopa and benserazide compound sustained-release three-layer tablet, provides a new compound for combined administration for treating Parkinson's disease (primary parkinsonism) and postencephalitic, arteriosclerotic or toxic parkinsonism syndrome, conveniently overcomes the defect of mutual influence of piribedil, levodopa and benserazide, and is convenient for patients to administer. The sustained-release preparation can ensure the long-acting release of the drugs and the stability of the drugs, and the tablet still has good stability under the environment with the relative humidity of 75% at 40 ℃ through the test of 6 months.
Detailed Description
The invention will be further illustrated and described with reference to specific embodiments. The technical features of the embodiments of the present invention can be combined correspondingly without mutual conflict.
Example 1:
the preparation method comprises the following steps:
(1) uniformly mixing the piribedil bulk drug and the first layer of croscarmellose sodium, sucrose and calcium carbonate in a mixer, adding a prepared adhesive solution containing polysorbate 80, performing wet granulation, drying and finishing wet granules, adding colloidal silicon dioxide and magnesium stearate, and uniformly mixing to obtain uniformly mixed first layer granules;
(2) uniformly mixing the second lamellar polyoxyethylene, sodium chloride, red ferric oxide and hydroxypropyl methylcellulose in a formula ratio in a mixer, performing dry granulation, adding magnesium stearate, and uniformly mixing to obtain second lamellar granules;
(3) uniformly mixing levodopa bulk drug and benserazide hydrochloride bulk drug with third-layer lactose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, hydroxypropyl cellulose and internally-added colloidal silicon dioxide in a mixer, performing dry granulation, adding colloidal silicon dioxide and magnesium stearate, and uniformly mixing to obtain third-layer particles;
(4) adding the obtained granules into corresponding slice layer charging hoppers respectively, and pressing into a three-layer slice to obtain a tablet core;
(5) coating a slow-release semipermeable membrane on a tablet core, aging properly, and punching holes on the upper surface and the lower surface of the tablet core by using a laser punching machine;
(6) finally, the coating is coated with a quick-release coating film.
Comparative example 1:
the preparation method comprises
(1) Uniformly mixing the piribedil bulk drug, croscarmellose sodium, sucrose and calcium carbonate in a mixer, adding a prepared adhesive solution containing polysorbate 80, performing wet granulation, and drying and finishing wet granules to obtain dried piribedil drug-containing granules; uniformly mixing levodopa bulk drug and benserazide hydrochloride bulk drug with lactose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, hydroxypropyl cellulose and internally-added colloidal silicon dioxide in a formula ratio in a mixer, performing dry granulation, adding piribedil-containing granules, colloidal silicon dioxide and magnesium stearate, and uniformly mixing to obtain third-layer granules;
(2) uniformly mixing the second lamellar polyoxyethylene, sodium chloride, red ferric oxide and hydroxypropyl methylcellulose in a formula ratio in a mixer, performing dry granulation, adding magnesium stearate, and uniformly mixing to obtain second lamellar granules;
(3) adding the obtained granules into corresponding slice layer charging hoppers respectively, and pressing into double-layer tablets to obtain tablet cores;
(4) coating a slow-release semipermeable membrane on a tablet core, aging properly, and punching a tablet core medicine-containing layer by using a laser punching machine;
(5) finally, the coating is coated with a quick-release coating film.
Comparative example 2:
the preparation method comprises
(1) Uniformly mixing the piribedil bulk drug and the first layer of croscarmellose sodium, sucrose and calcium carbonate in a mixer, adding a prepared adhesive solution containing polysorbate 80, performing wet granulation, drying and finishing wet granules, adding colloidal silicon dioxide and magnesium stearate, and uniformly mixing to obtain uniformly mixed first layer granules;
(2) uniformly mixing the second lamellar polyoxyethylene, sodium chloride, red ferric oxide and hydroxypropyl methylcellulose in a formula ratio in a mixer, performing dry granulation, adding magnesium stearate, and uniformly mixing to obtain second lamellar granules;
(3) adding the obtained granules into corresponding slice layer charging hoppers respectively, and pressing into double-layer tablets to obtain tablet cores;
(4) coating a slow-release semipermeable membrane on a tablet core, aging properly, and punching a tablet core medicine-containing layer by using a laser punching machine;
(5) finally, the coating is coated with a quick-release coating film.
Comparative example 3:
the preparation method comprises the following steps:
(1) uniformly mixing levodopa bulk drug and benserazide hydrochloride bulk drug with a first layer of lactose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, hydroxypropyl cellulose and internally added colloidal silicon dioxide in a mixer, granulating by a dry method, adding colloidal silicon dioxide and magnesium stearate, and uniformly mixing to obtain first layer granules;
(2) uniformly mixing the second lamellar polyoxyethylene, sodium chloride, red ferric oxide and hydroxypropyl methylcellulose in a formula ratio in a mixer, performing dry granulation, adding magnesium stearate, and uniformly mixing to obtain second lamellar granules;
(3) adding the obtained granules into corresponding slice layer charging hoppers respectively, and pressing into double-layer tablets to obtain tablet cores;
(4) coating a slow-release semipermeable membrane on a tablet core, aging properly, and punching a tablet core medicine-containing layer by using a laser punching machine;
(5) finally, the coating is coated with a quick-release coating film.
The comparison of the dissolution curve data of example 1 and comparative examples 1-3 is as follows:
table 1: piribedil dissolution data
| Dissolution amount of piribedil% | 1h | 2h | 4h | 8h | 12h |
| Example 1 | 18.96 | 35.29 | 58.67 | 85.66 | 98.21 |
| Comparative example 1 | 13.54 | 25.68 | 47.03 | 77.19 | 97.24 |
| Comparative example 2 | 19.25 | 38.72 | 60.24 | 89.64 | 99.57 |
Table 2: levodopa dissolution data
| Dissolution amount of levodopa% | 1h | 2h | 4h | 8h | 12h |
| Example 1 | 15.27 | 33.58 | 70.29 | 91.58 | 101.53 |
| Comparative example 1 | 13.54 | 48.51 | 86.49 | 98.51 | 103.4 |
| Comparative example 3 | 16.38 | 35.60 | 68.33 | 94.37 | 99.79 |
Table 3: benserazide dissolution data
| Benserazide dissolution amount% | 1h | 2h | 4h | 8h | 12h |
| Example 1 | 11.58 | 30.89 | 60.37 | 87.55 | 101.11 |
| Comparative example 1 | 5.61 | 16.87 | 48.31 | 76.66 | 99.64 |
| Comparative example 3 | 13.67 | 34.56 | 64.83 | 89.82 | 102.04 |
From the experimental results in the table, the dissolution tendency of the piribedil tablet prepared in the embodiment 1 of the invention is basically consistent with that of the comparative example 2 of the piribedil sustained-release tablet; the dissolution tendency of levodopa and benserazide is basically consistent with that of comparative example 3. In the comparative example 1, the dissolving trends of the piribedil, the levodopa and the benserazide are too slow, the medicine dissolving amount in a specified time cannot be ensured, and the effective treatment effect of the medicine cannot be achieved. In comparative example 1, the difference between tablets is too large, and the RSD exceeds 10 at the first three time points, so that the dissolution of each tablet is not qualified. The results of comparing the accelerated stability data of example 1 with those of comparative examples 1 to 3 are as follows:
table 4: content stability data at 40 ℃ accelerated conditions
Table 4: impurity stability data at 40 ℃ accelerated conditions
From the experimental results in the table above, it can be seen that the tablet prepared in the embodiment 1 of the present invention has good stability under the accelerated test condition at 40 ℃, is basically consistent with the stability of the piribe comparative examples 2-3, and is obviously superior to the compound preparation without the isolation layer in the comparative example 1; the impurity increment of the embodiment 1 is less, is slightly better than that of the comparative examples 2-3, and is obviously better than that of the compound preparation without the isolation layer of the comparative example 1.
Claims (10)
1. The compound sustained-release three-layer tablet containing the piribedil, the levodopa and the benserazide is characterized in that the tablet is an osmotic pump type sustained-release tablet and is divided into a tablet core and a coating film, wherein the tablet core is divided into three layers, namely a first layer containing the active ingredient piribedil, a second layer serving as an isolation layer or a boosting layer and a third layer containing the active ingredient levodopa and the benserazide.
2. The compound sustained-release three-layer tablet of piribedil, levodopa and benserazide according to claim 1, characterized in that the second layer is an isolation layer for dividing the drug-containing layer of piribedil and the drug-containing layer of levodopa and benserazide, and is also used as a boosting layer of the sustained-release tablet.
3. The compound sustained-release three-layer tablet of piribedil, levodopa and benserazide according to claim 1, which is characterized in that the mass ratio of the three active ingredients of piribedil, levodopa and benserazide is 30-70: 150-250: 25-80.
4. The piribedil, levodopa and benserazide compound sustained-release three-layer tablet according to claim 1, wherein the benserazide is present in the tablet as a hydrochloride salt.
5. The piribedil, levodopa and benserazide compound sustained-release three-layer tablet according to claim 1, characterized in that the coating film comprises a sustained-release semipermeable membrane and an immediate-release coating film, and the immediate-release coating film is coated outside the sustained-release semipermeable membrane.
6. The piribedil, levodopa and benserazide compound sustained-release three-layer tablet according to claim 5, wherein the sustained-release semipermeable membrane material is ethyl cellulose or cellulose acetate, and the adopted pore-forming agent is polyethylene glycol; the weight increment range of the slow-release semipermeable membrane reaches 6-12% of the tablet core.
7. The piribedil, levodopa and benserazide compound sustained-release three-layer tablet according to claim 5, characterized in that the quick-release coating film is coated outside the sustained-release semipermeable membrane, a gastric-soluble coating powder is adopted, and the weight increment range of the quick-release coating film reaches 1-3% of that of the tablet core.
8. The piribedil, levodopa and benserazide compound sustained-release three-layer tablet according to claim 1, wherein the first layer comprises piribedil and pharmaceutically acceptable auxiliary materials, and the second layer comprises polyoxyethylene, sodium chloride, red iron oxide, hypromellose and magnesium stearate; the third sheet layer comprises levodopa, benserazide hydrochloride and pharmaceutically acceptable auxiliary materials.
9. The compound sustained-release three-layer tablet of piribedil, levodopa and benserazide according to claim 1, characterized in that the first layer comprises the following components by mass:
the second slice composition by mass is as follows:
the third slice composition by mass is as follows:
the coating film comprises the following components in percentage by mass:
slow release semipermeable membranes: 28-70 parts of cellulose acetate
2-6 parts of polyethylene glycol
Quick-release coating film: 5-20 parts of gastric coating powder.
10. A method for preparing the piribedil, levodopa and benserazide compound sustained-release three-layer tablet according to claim 9, which is characterized by comprising the following steps:
uniformly mixing the piribedil bulk drug, the first tablet disintegrating agent, the filler and the stabilizer in a formula ratio in a mixer, adding the prepared binder solution containing the solubilizer, performing wet granulation, drying and finishing wet granules, adding the lubricant, and uniformly mixing to obtain uniformly mixed first tablet granules;
uniformly mixing the second lamellar polyoxyethylene, sodium chloride, red ferric oxide and hydroxypropyl methylcellulose in a formula ratio in a mixer, performing dry granulation, adding magnesium stearate, and uniformly mixing to obtain second lamellar granules;
uniformly mixing the levodopa bulk drug and the benserazide hydrochloride bulk drug with the third-layer disintegrating agent, the filling agent and the adhesive in a formula ratio in a mixer, performing dry granulation, adding the lubricant, and uniformly mixing to obtain third-layer particles;
adding the obtained granules into corresponding slice layer charging hoppers respectively, and pressing into a three-layer slice to obtain a tablet core;
coating a slow-release semipermeable membrane on a tablet core, aging properly, and punching holes on the upper surface and the lower surface of the tablet core by using a laser punching machine;
finally, the coating is coated with a quick-release coating film.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010087042.9A CN111084777A (en) | 2020-02-11 | 2020-02-11 | Piribedil, levodopa and benserazide compound sustained-release three-layer tablet and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010087042.9A CN111084777A (en) | 2020-02-11 | 2020-02-11 | Piribedil, levodopa and benserazide compound sustained-release three-layer tablet and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111084777A true CN111084777A (en) | 2020-05-01 |
Family
ID=70399853
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010087042.9A Pending CN111084777A (en) | 2020-02-11 | 2020-02-11 | Piribedil, levodopa and benserazide compound sustained-release three-layer tablet and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111084777A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024120389A1 (en) * | 2022-12-05 | 2024-06-13 | 上海汉都医药科技有限公司 | Delayed timed release pharmaceutical composition, preparation method therefor, and use thereof |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060189694A1 (en) * | 2004-11-24 | 2006-08-24 | Went Gregory T | Composition and method for treating neurological disease |
| CN101161242A (en) * | 2006-10-13 | 2008-04-16 | 北京红林制药有限公司 | A explosive core composition of controlled release administer drug and controlled release preparation as well as its preparing method |
| CN101987083A (en) * | 2010-07-16 | 2011-03-23 | 钟术光 | Preparation method for controlled release preparation, especial for zero-order release controlled release preparation |
| EP2918266A1 (en) * | 2014-03-11 | 2015-09-16 | CDRD Berolina AB | Composition comprising a dopamine agonist and an L-DOPA derivative for treating Parkinson's disease |
| CN105534938A (en) * | 2016-01-24 | 2016-05-04 | 宁夏康亚药业有限公司 | Piribedil hydrophilic gel membrane controlled and sustained release reparation and preparation method thereof |
| AU2017297718A1 (en) * | 2016-07-11 | 2019-01-31 | Contera Pharma A/S | Pulsatile drug delivery system for treating morning akinesia |
| CN109432034A (en) * | 2018-12-28 | 2019-03-08 | 乐普制药科技有限公司 | A kind of valsartan amlodipine tri-layer tablets and preparation method thereof |
| WO2019165993A1 (en) * | 2018-02-28 | 2019-09-06 | 上海汉都医药科技有限公司 | Pharmaceutical composition and preparation method therefor and use thereof |
| CN113425847A (en) * | 2020-03-23 | 2021-09-24 | 上海汉都医药科技有限公司 | Tablet coating film, raw material composition and preparation thereof, controlled-release tablet and preparation thereof |
-
2020
- 2020-02-11 CN CN202010087042.9A patent/CN111084777A/en active Pending
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060189694A1 (en) * | 2004-11-24 | 2006-08-24 | Went Gregory T | Composition and method for treating neurological disease |
| CN101161242A (en) * | 2006-10-13 | 2008-04-16 | 北京红林制药有限公司 | A explosive core composition of controlled release administer drug and controlled release preparation as well as its preparing method |
| CN101987083A (en) * | 2010-07-16 | 2011-03-23 | 钟术光 | Preparation method for controlled release preparation, especial for zero-order release controlled release preparation |
| EP2918266A1 (en) * | 2014-03-11 | 2015-09-16 | CDRD Berolina AB | Composition comprising a dopamine agonist and an L-DOPA derivative for treating Parkinson's disease |
| CN105534938A (en) * | 2016-01-24 | 2016-05-04 | 宁夏康亚药业有限公司 | Piribedil hydrophilic gel membrane controlled and sustained release reparation and preparation method thereof |
| AU2017297718A1 (en) * | 2016-07-11 | 2019-01-31 | Contera Pharma A/S | Pulsatile drug delivery system for treating morning akinesia |
| CN109689036A (en) * | 2016-07-11 | 2019-04-26 | 康特拉医药公司 | For treating morning akinetic pulse delivery system |
| WO2019165993A1 (en) * | 2018-02-28 | 2019-09-06 | 上海汉都医药科技有限公司 | Pharmaceutical composition and preparation method therefor and use thereof |
| CN109432034A (en) * | 2018-12-28 | 2019-03-08 | 乐普制药科技有限公司 | A kind of valsartan amlodipine tri-layer tablets and preparation method thereof |
| CN113425847A (en) * | 2020-03-23 | 2021-09-24 | 上海汉都医药科技有限公司 | Tablet coating film, raw material composition and preparation thereof, controlled-release tablet and preparation thereof |
Non-Patent Citations (5)
| Title |
|---|
| 唐星,等: "《口服缓控释制剂》", 31 January 2007, 人民卫生出版社, pages: 206 - 207 * |
| 巩晓英,等: "多巴丝肼联合吡贝地尔治疗帕金森病的效果", 《临床医学研究与实践》 * |
| 巩晓英,等: "多巴丝肼联合吡贝地尔治疗帕金森病的效果", 《临床医学研究与实践》, vol. 1, no. 20, 20 October 2016 (2016-10-20), pages 1 * |
| 李伟: ""渗透泵控释制剂产业化中创新性制备技术的研究与评价"", 《中国博士学位论文全文数据库工程科技Ⅰ辑》, vol. 2016, no. 05, pages 528 - 530 * |
| 梅长林,等: "《中国内科年鉴》", 31 March 2011, 第二军医大学出版社, pages: 540 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024120389A1 (en) * | 2022-12-05 | 2024-06-13 | 上海汉都医药科技有限公司 | Delayed timed release pharmaceutical composition, preparation method therefor, and use thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110548026B (en) | Pharmaceutical composition containing glucokinase activator and K-ATP channel blocker, and preparation method and application thereof | |
| TWI241911B (en) | Sustained release ranolazine formulations | |
| KR100760430B1 (en) | Controlled release complex formulation for oral administration of medicine for diabetes and method for the preparation thereof | |
| JP6173521B2 (en) | Formulations containing nalbuphine and their use | |
| EP2486918A2 (en) | Pharmaceutical composition with both immediate and extended release characteristics | |
| MXPA00012957A (en) | Extended release oral dosage composition. | |
| US20080181946A1 (en) | Controlled Release Delivery System For Metformin | |
| CN113018273B (en) | Solid preparation and preparation method and application thereof | |
| KR20130126253A (en) | Sustained-release combination preparations for the treatment of diabetes mellitus having enhanced compliance and preparation method thereof | |
| CN110623934B (en) | Trimetazidine hydrochloride sustained release tablet and preparation method thereof | |
| CN111084777A (en) | Piribedil, levodopa and benserazide compound sustained-release three-layer tablet and preparation method thereof | |
| CN102247366B (en) | Medicinal compositionslow-releaseformulation containing Enalapril and Felodipine | |
| CN110251473A (en) | Hydroxyl piperazine pyrrone oral slow-releasing preparation | |
| CN102755310A (en) | Composition drug preparation containing levodopa | |
| CN114224859B (en) | Compound antihypertensive pharmaceutical composition and preparation method thereof | |
| KR101265491B1 (en) | Dissolution rate controlled multilayered tablet for oral administration containing sarpogrelate hydrochloride and manufacturing method thereof | |
| CN106890166B (en) | Skin external preparation containing calcium receptor active compound | |
| WO2014096982A1 (en) | Stable pharmaceutical compositions of saxagliptin or salts thereof | |
| WO2019132833A1 (en) | The modified release combination comprising linagliptin and metformin | |
| CN114306263B (en) | Compound antihypertensive pharmaceutical composition and preparation method thereof | |
| RU2798106C1 (en) | Pharmaceutical composition containing ethylmethylhydroxypyridine succinate | |
| KR20190075718A (en) | Multi-layer solid formulation with enhanced dissolution rate comprising tramadol or pharmaceutically acceptable salt thereof and pregabalin or pharmaceutically acceptable salt thereof | |
| WO2021036230A1 (en) | Ranolazine sustained-release composition and preparation method therefor | |
| CN109316455B (en) | Trimetazidine hydrochloride sustained release tablet | |
| WO2011027322A1 (en) | Extended release dosage form containing olopatadine for oral administration |
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 | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200501 |