CN116637091A - Artesunate-Bopa ethanolamine oral-dissolving film and preparation method and application thereof - Google Patents
Artesunate-Bopa ethanolamine oral-dissolving film and preparation method and application thereof Download PDFInfo
- Publication number
- CN116637091A CN116637091A CN202310903783.3A CN202310903783A CN116637091A CN 116637091 A CN116637091 A CN 116637091A CN 202310903783 A CN202310903783 A CN 202310903783A CN 116637091 A CN116637091 A CN 116637091A
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- CN
- China
- Prior art keywords
- ethanolamine
- film
- oral
- qubo
- eltrombopag
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- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 title claims abstract description 168
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- FMLGTJWOWQEDOC-UHFFFAOYSA-N 2-aminoethanol 3-[3-[[2-(3,4-dimethylphenyl)-5-methyl-3-oxo-1H-pyrazol-4-yl]diazenyl]-2-hydroxyphenyl]benzoic acid Chemical compound CC1=C(C=C(C=C1)N2C(=O)C(=C(N2)C)N=NC3=CC=CC(=C3O)C4=CC(=CC=C4)C(=O)O)C.C(CO)N FMLGTJWOWQEDOC-UHFFFAOYSA-N 0.000 claims abstract description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 42
- 229940100688 oral solution Drugs 0.000 claims abstract description 36
- 239000003814 drug Substances 0.000 claims abstract description 34
- 239000000463 material Substances 0.000 claims abstract description 25
- 239000002904 solvent Substances 0.000 claims abstract description 19
- 239000004014 plasticizer Substances 0.000 claims abstract description 18
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 15
- 239000002245 particle Substances 0.000 claims abstract description 13
- 201000010099 disease Diseases 0.000 claims abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
- 230000001404 mediated effect Effects 0.000 claims abstract description 9
- 108060003951 Immunoglobulin Proteins 0.000 claims abstract description 6
- 239000003862 glucocorticoid Substances 0.000 claims abstract description 6
- 102000018358 immunoglobulin Human genes 0.000 claims abstract description 6
- 206010043554 thrombocytopenia Diseases 0.000 claims abstract description 6
- 238000002156 mixing Methods 0.000 claims description 44
- 239000007788 liquid Substances 0.000 claims description 40
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 35
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 35
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 35
- 239000012528 membrane Substances 0.000 claims description 29
- 238000001035 drying Methods 0.000 claims description 28
- 239000000725 suspension Substances 0.000 claims description 28
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 13
- 229930195725 Mannitol Natural products 0.000 claims description 13
- 235000011187 glycerol Nutrition 0.000 claims description 13
- 239000000594 mannitol Substances 0.000 claims description 13
- 235000010355 mannitol Nutrition 0.000 claims description 13
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 12
- 238000000576 coating method Methods 0.000 claims description 12
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 12
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 12
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 239000011248 coating agent Substances 0.000 claims description 11
- 229960003943 hypromellose Drugs 0.000 claims description 10
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 9
- 239000000796 flavoring agent Substances 0.000 claims description 9
- 235000013355 food flavoring agent Nutrition 0.000 claims description 9
- 239000000661 sodium alginate Substances 0.000 claims description 9
- 235000010413 sodium alginate Nutrition 0.000 claims description 9
- 229940005550 sodium alginate Drugs 0.000 claims description 9
- 239000002994 raw material Substances 0.000 claims description 8
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 claims description 7
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 7
- 229920002774 Maltodextrin Polymers 0.000 claims description 7
- 239000005913 Maltodextrin Substances 0.000 claims description 7
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 7
- 239000008101 lactose Substances 0.000 claims description 7
- 229940035034 maltodextrin Drugs 0.000 claims description 7
- 229960003194 meglumine Drugs 0.000 claims description 7
- 229920001993 poloxamer 188 Polymers 0.000 claims description 7
- 229940044519 poloxamer 188 Drugs 0.000 claims description 7
- IELOKBJPULMYRW-NJQVLOCASA-N D-alpha-Tocopheryl Acid Succinate Chemical compound OC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C IELOKBJPULMYRW-NJQVLOCASA-N 0.000 claims description 6
- 229940099418 d- alpha-tocopherol succinate Drugs 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 6
- 229920000053 polysorbate 80 Polymers 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 4
- 239000004386 Erythritol Substances 0.000 claims description 4
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 claims description 4
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 claims description 4
- 235000019414 erythritol Nutrition 0.000 claims description 4
- 229940009714 erythritol Drugs 0.000 claims description 4
- 239000003361 porogen Substances 0.000 claims description 4
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 3
- 229940068984 polyvinyl alcohol Drugs 0.000 claims description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 3
- 229940083575 sodium dodecyl sulfate Drugs 0.000 claims description 2
- 239000008186 active pharmaceutical agent Substances 0.000 claims 3
- 229940079593 drug Drugs 0.000 abstract description 21
- 238000004090 dissolution Methods 0.000 abstract description 9
- 230000007547 defect Effects 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 50
- 238000004321 preservation Methods 0.000 description 16
- 238000010438 heat treatment Methods 0.000 description 12
- 238000011068 loading method Methods 0.000 description 12
- 239000008213 purified water Substances 0.000 description 12
- 239000004376 Sucralose Substances 0.000 description 11
- 235000019408 sucralose Nutrition 0.000 description 11
- 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 description 11
- 238000005520 cutting process Methods 0.000 description 8
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 3
- 230000000630 rising effect Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- QBUKAFSEUHGMMX-MTJSOVHGSA-N (5z)-5-[[3-(1-hydroxyethyl)thiophen-2-yl]methylidene]-10-methoxy-2,2,4-trimethyl-1h-chromeno[3,4-f]quinolin-9-ol Chemical compound C1=CC=2NC(C)(C)C=C(C)C=2C2=C1C=1C(OC)=C(O)C=CC=1O\C2=C/C=1SC=CC=1C(C)O QBUKAFSEUHGMMX-MTJSOVHGSA-N 0.000 description 2
- TXFGIQHSKUINRC-UHFFFAOYSA-N 2-[2-[2-[[[2-(4-bromothiophen-2-yl)-2-hydroxyethyl]amino]methyl]phenoxy]ethyl]isoindole-1,3-dione Chemical compound C=1C=CC=C(OCCN2C(C3=CC=CC=C3C2=O)=O)C=1CNCC(O)C1=CC(Br)=CS1 TXFGIQHSKUINRC-UHFFFAOYSA-N 0.000 description 2
- 102000005763 Thrombopoietin Receptors Human genes 0.000 description 2
- 108010070774 Thrombopoietin Receptors Proteins 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 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 description 2
- 210000003593 megakaryocyte Anatomy 0.000 description 2
- 238000011056 performance test Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- FIINVRHWVBUYAJ-UHFFFAOYSA-N 2-[(2-methoxyphenyl)methylamino]-1-[3-(trifluoromethoxy)phenyl]ethanol Chemical compound COC1=CC=CC=C1CNCC(O)C1=CC=CC(OC(F)(F)F)=C1 FIINVRHWVBUYAJ-UHFFFAOYSA-N 0.000 description 1
- 239000000120 Artificial Saliva Substances 0.000 description 1
- 229920002556 Polyethylene Glycol 300 Polymers 0.000 description 1
- UEDUENGHJMELGK-HYDKPPNVSA-N Stevioside Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UEDUENGHJMELGK-HYDKPPNVSA-N 0.000 description 1
- 102100034195 Thrombopoietin Human genes 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- GMVLGJDMPCRIJK-CGZBRXJRSA-N benzyl n-[(2s)-1-[(3-hydroxyoxan-4-yl)amino]-4-methyl-1-oxopentan-2-yl]carbamate Chemical compound N([C@@H](CC(C)C)C(=O)NC1C(COCC1)O)C(=O)OCC1=CC=CC=C1 GMVLGJDMPCRIJK-CGZBRXJRSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 210000003643 myeloid progenitor cell Anatomy 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- -1 stevioside Chemical compound 0.000 description 1
- 229940013618 stevioside Drugs 0.000 description 1
- OHHNJQXIOPOJSC-UHFFFAOYSA-N stevioside Natural products CC1(CCCC2(C)C3(C)CCC4(CC3(CCC12C)CC4=C)OC5OC(CO)C(O)C(O)C5OC6OC(CO)C(O)C(O)C6O)C(=O)OC7OC(CO)C(O)C(O)C7O OHHNJQXIOPOJSC-UHFFFAOYSA-N 0.000 description 1
- 235000019202 steviosides Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 230000004797 therapeutic response Effects 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
- A61K9/0012—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
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7007—Drug-containing films, membranes or sheets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention provides an iderobopamine oral solution film, a preparation method and application thereof, and relates to the technical field of pharmaceutical preparations. The eltrombopag ethanolamine oral soluble film provided by the invention comprises the following dry-basis components in percentage by mass: ai Qubo Pa ethanolamine 20-40%, film forming material 20-40%, plasticizer 10-20%, pore-forming agent 5-20% and solubilizer 1-10%; in oral dissolving filmThe mass content of water is 3-8%; d of the Ai Qubo Pa ethanolamine 90 Particle size is less than or equal to 10 mu m. The eltrombopag ethanolamine oral film provided by the invention has the advantages of high disintegration speed, high dissolution rate, good flexibility, good taste and excellent comprehensive performance, overcomes the defects of inaccurate dosage, inconvenient administration and the like of the traditional eltrombopag ethanolamine medicine, uses a small amount of auxiliary materials, is quick to disintegrate, does not need water to take, is convenient to take, and has good application prospects in the aspects of preparing glucocorticoid, immunoglobulin-mediated diseases and thrombocytopenia medicines.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to an iderpopamine oral solution film, a preparation method and application thereof.
Background
At present, the development trend of the oral instant film is to improve the drug loading rate and develop the film formation of insoluble drugs. Where drug loading is generally controlled by increasing size and thickness, this may lead to embrittlement of the orosol film, slow disintegration, and thus affect the properties of the orosol film and patient compliance. Blind pursuit of high drug loading can affect the mechanical properties of an orosol film, such as disintegration time, tensile strength, etc. This approach can even lead to recrystallization of the amorphous pharmaceutical active ingredient (API) in the final dosage form after solvent evaporation or during long-term storage.
When the insoluble medicine is prepared into an oral solution film, the uniformity and mechanical property of the film are difficult to control. When hypromellose is used as the film forming material, even a high dosage of poorly soluble drug can obtain a good content uniformity (30% dry film mass is equivalent to 5mg/1.5 cm) 2 The dose of (2) but the in vitro disintegration time exceeds 100 seconds, which does not meet the requirement of 30 seconds disintegration. The API and other components form ion pairs, such as ibuprofen-ethanolamine, so that the solubility of the medicine in the copolymer solvent is improved, the API is uniformly dispersed in the membrane liquid, and the dissolution rate of the medicine is increased.
Ai Qubo Paethanolamine is a non-peptide oral thrombopoietin receptor (TPO-R) agonist, and the marketed dosage forms comprise tablets and dry suspensions, have the specification of 12.5mg, 25mg, 50mg and 75mg, can be combined with TPO receptors (transmembrane regions) on cell membranes, activate signal transduction pathways, stimulate differentiation and proliferation of human myeloid progenitor cells into megakaryocytes, promote megakaryocyte maturation, and further increase the generation of platelets, and are suitable for adults with poor therapeutic response to glucocorticoids, immunoglobulins and the like and chronic immune (idiopathic) thrombocytopenia (ITP) patients of children over 12 years old, so that the platelet count is increased, and bleeding is reduced or prevented. However, ai Qubo Pa ethanolamine is a drug with poor solubility and pH dependence, and has a large initial dose, and the dosage in the taking period needs to be adjusted frequently, so that the effect on the taking compliance of the old and children is large. The preparation of Ai Qubo Pa ethanolamine into an oral film of eltrombopag ethanolamine can improve the administration convenience and the administration compliance, however, no report on the oral film of eltrombopag ethanolamine is currently available.
Disclosure of Invention
In view of the above, the invention aims to provide an oral dissolved film of eltrombopag ethanolamine, a preparation method and application thereof, and solves the problems of low drug loading rate and indissolvable property of the raw material drug of eltrombopag ethanolamine.
In order to achieve the above object, the present invention provides the following technical solutions.
The invention provides an oral dissolved film of eltrombopag ethanolamine, which comprises the following dry-basis components in percentage by mass: ai Qubo Pa ethanolamine 20-40%, film forming material 20-40%, plasticizer 10-20%, pore-forming agent 5-20% and solubilizer 1-10%; the mass content of water in the eltrombopag ethanolamine oral dissolved film is 3-8%; d of the Ai Qubo Pa ethanolamine 90 Particle size is less than or equal to 10 mu m.
Preferably, the thickness of the eltrombopag ethanolamine oral solution film is 0.06-0.17 mm, the length is 3-3.5 cm, and the width is 2-2.5 cm.
Preferably, the film-forming material comprises at least one of hypromellose, polyvinyl alcohol, maltodextrin and sodium alginate.
Preferably, the plasticizer includes at least one of glycerin, polyvinyl alcohol and propylene glycol.
Preferably, the porogen comprises at least one of lactose, erythritol and mannitol.
Preferably, the solubilizing agent comprises at least one of poloxamer 188, tween 80, sodium dodecyl sulfate, vitamin E succinate and meglumine.
Preferably, the components of the eltrombopag ethanolamine oral solution film also comprise less than 5% of flavoring agent by mass percent.
The invention provides a preparation method of an eltrombopag ethanolamine oral dissolving film, which comprises the following steps: (1) First mixing Ai Qubo Pa ethanolamine, a plasticizer, a solubilizer, a pore-forming agent and water to obtain an API suspension; (2) Secondly mixing a film forming material with water to obtain a base film liquid; (3) Thirdly mixing the API suspension with the base film liquid, and drying after coating to obtain an eltrombopag ethanolamine oral solution film; the step (1) and the step (2) have no time sequence.
Preferably, the solid content of the API suspension is 5-20%; the solid content of the base film liquid is 5-10%; the rotation speeds of the first mixing, the second mixing and the third mixing are independently 100-300 rpm, and the time is independently 1-2 h.
The invention provides an application of the eltrombopag ethanolamine oral dissolved film in the technical scheme or the eltrombopag ethanolamine oral dissolved film prepared by the preparation method in the technical scheme in preparing medicines for treating glucocorticoid-mediated diseases, immunoglobulin-mediated diseases or thrombocytopenia.
The beneficial technical effects are as follows: according to the invention, ai Qubo Pa ethanolamine is used as a raw material medicine, the particle size of Ai Qubo Pa ethanolamine is controlled, so that the particle feel of the raw material medicine is improved, the film forming effect of a film forming material is improved, the medicine carrying capacity of a Ai Qubo Pa ethanolamine oral soluble film is high, and the problems of low medicine carrying capacity and indissolvable raw material medicine are solved; the plasticizer can improve the flexibility of the eltrombopag ethanolamine oral film; the pore-forming agent can increase the disintegration speed of the oral dissolved film of the eltrombopag ethanolamine and the dissolution rate of Ai Qubo Pa ethanolamine; the solubilizer can improve the dispersion uniformity of Ai Qubo Pa ethanolamine in Ai Qubo Pa ethanolamine mouth-soluble film; under the combined action of Ai Qubo Pa ethanolamine, a film forming material, a plasticizer, a pore-forming agent and a solubilizer, the eltrombopag ethanolamine oral solution has the advantages of high disintegration speed, high dissolution rate, good flexibility, good taste and excellent comprehensive performance, overcomes the defects of inaccurate dosage, inconvenient administration and the like of the traditional eltrombopag ethanolamine medicine, uses less amount of auxiliary materials (the film forming material, the plasticizer, the pore-forming agent, the solubilizer and the flavoring agent), can be rapidly disintegrated in an oral cavity, does not need water for taking, is convenient for taking, has high patient taking compliance, and has good application prospect in preparing medicines for treating glucocorticoid-mediated diseases, immunoglobulin-mediated diseases or thrombocytopenia.
The preparation method provided by the invention has simple and controllable process, and can prepare the oral instant film containing Ai Qubo Pa ethanolamine which is a large-sized and insoluble raw material medicine without special production equipment; the API suspension has viscosity, ai Qubo Pa ethanolamine is not easy to settle and is uniformly dispersed, and the API suspension and the base film liquid are mixed to form a film, so that Ai Qubo Pa ethanolamine in the oral solution film has high dispersion uniformity, and the oral dispersion film agent of the oral solution film has good flexibility, quick disintegration, good taste, high medicine taking dependency and low production cost, and is suitable for industrial mass production.
Detailed Description
The invention provides an oral dissolved film of eltrombopag ethanolamine, which comprises the following dry-basis components in percentage by mass: ai Qubo Pa ethanolamine 20-40%, film forming material 20-40%, plasticizer 10-20%, pore-forming agent 5-20% and solubilizer 1-10%; the mass content of water in the eltrombopag ethanolamine oral dissolved film is 3-8%; d of the Ai Qubo Pa ethanolamine 90 Particle size is less than or equal to 10 mu m.
The dry-based component of the eltrombopag ethanolamine oral solution film provided by the invention comprises 20-40%, preferably 25-35%, more preferably 25-30% of Ai Qubo Pa ethanolamine. In the present invention, the Ai Qubo Pa ethanolamine D 90 Particle size is less than or equal to 10 mu m.
The dry-based component of the eltrombopag ethanolamine oral solution film provided by the invention comprises 20-40% of film forming materials, preferably 30-40%, and more preferably 35-40%. In the present invention, the film-forming material preferably includes at least one of hypromellose, polyvinyl alcohol, maltodextrin, and sodium alginate, more preferably a mixture of polyvinyl alcohol and hypromellose, a mixture of polyvinyl alcohol and maltodextrin, a mixture of polyvinyl alcohol and sodium alginate, or polyvinyl alcohol; the mass ratio of the polyvinyl alcohol to the hydroxypropyl methylcellulose in the mixture of the polyvinyl alcohol and the hydroxypropyl methylcellulose is preferably 1:1 to 5, more preferably 1: 1-3; the mass ratio of the polyvinyl alcohol to the maltodextrin in the mixture of the polyvinyl alcohol and the maltodextrin is preferably 1:1 to 5, more preferably 1:2 to 4, more preferably 1:3; the mass ratio of the polyvinyl alcohol to the sodium alginate in the mixture of the polyvinyl alcohol and the sodium alginate is preferably 1:1 to 5, more preferably 1:2 to 4, more preferably 1:3; the polyvinyl alcohol preferably comprises one or more of EG-05P, EG-03P and EG-18P. In the invention, the polyvinyl alcohol is used as a film forming material and has high drug loading, and the polyvinyl alcohol is compounded with other film forming materials (at least one of hypromellose, maltodextrin and sodium alginate), so that the drug loading and mechanical properties of the oral film can be further improved, and the application of the polyvinyl alcohol to disintegration of the oral film and dissolution of the eltrombopag ethanolamine due to the slow release effect of the polyvinyl alcohol can be avoided by controlling the dosage ratio of the polyvinyl alcohol to the other film forming materials.
The dry-based component of the eltrombopag ethanolamine oral solution film provided by the invention comprises 10-20% of plasticizer, preferably 12-18%, and more preferably 14-15%. In the present invention, the preferred plasticizer preferably includes at least one of glycerin, polyethylene glycol, and propylene glycol, more preferably glycerin, polyethylene glycol, or propylene glycol; the polyethylene glycol preferably comprises PEG400 and/or PEG300.
The dry-based component of the eltrombopag ethanolamine oral solution film provided by the invention comprises 5-20% of pore-forming agent, preferably 10-20%, and more preferably 15-18%. In the present invention, the porogen preferably includes at least one of lactose, erythritol and mannitol, and more preferably lactose, erythritol or mannitol.
The dry-based component of the eltrombopag ethanolamine oral solution film provided by the invention comprises 1-10% of a solubilizer, preferably 2-6%, and more preferably 2-5%. In the present invention, the solubilizing agent preferably includes at least one of poloxamer 188, tween 80, sodium lauryl sulfate, vitamin E succinate and meglumine.
The dry-based component of the eltrombopag ethanolamine oral solution film provided by the invention preferably further comprises 5% of a flavoring agent, preferably 0.5-3%, and more preferably 1-2% by mass. In the present invention, the flavoring agent preferably includes at least one of sucralose, such as stevioside, orange peel syrup, and sodium chloride, more preferably sucralose or sodium chloride; the taste modifier can improve the taste of the eltrombopag ethanolamine oral dissolving film.
In the invention, the mass content of water in the eltrombopag ethanolamine oral solution film is 3-8%, preferably 4-7%, more preferably 5-6%. In the invention, the thickness of the eltrombopag ethanolamine oral solution film is preferably 0.06-0.17 mm, more preferably 0.07-0.16 mm, particularly preferably 0.06mm, 0.07mm, 0.08mm, 0.09mm, 0.1mm, 0.11mm, 0.12mm, 0.13mm, 0.14mm, 0.15mm, 0.16mm or 0.17mm; the length of the eltrombopag ethanolamine oral dissolving film is preferably 3-3.5 cm, and particularly preferably 3cm, 3.1cm, 3.2cm, 3.3cm, 3.4cm or 3.5cm; the width of the eltrombopag ethanolamine oral dissolving film is preferably 2-2.5 cm, and particularly preferably 2cm, 2.1cm, 2.2cm, 2.3cm, 2.4cm or 2.5cm; the width x length of the eltrombopag ethanolamine oral solution film is more preferably 2cm x 3cm, 2.5cm x 3cm or 2cm x 3.5cm.
The invention provides a preparation method of an eltrombopag ethanolamine oral dissolving film, which comprises the following steps: (1) First mixing Ai Qubo Pa ethanolamine, a plasticizer, a solubilizer, a pore-forming agent and water to obtain an API suspension; (2) Secondly mixing a film forming material with water to obtain a base film liquid; (3) Thirdly mixing the API suspension with the base film liquid, and drying after coating to obtain an eltrombopag ethanolamine oral solution film; the step (1) and the step (2) have no time sequence.
The raw materials adopted by the invention are all commercial products unless specified.
According to the invention, ai Qubo Pa ethanolamine, a plasticizer, a solubilizer, a pore-forming agent and water are mixed for the first time to obtain an API suspension.
In the present invention, when the components of the eltrombopag ethanolamine oral solution further comprise a flavoring agent, the first mixing is preferably a first mixing of the rotrap ethanolamine, the plasticizer, the solubilizer, the porogen, the flavoring agent and the water.
In the present invention, the first mixing is preferably stirring mixing; the stirring and mixing speed is preferably 100 to 300rpm, more preferably 150 to 250rpm, and even more preferably 200rpm; the time of the first mixing is preferably 1 to 2 hours, more preferably 1.5 hours. In the present invention, the order of the first mixing is preferably mixing Ai Qubo Pa ethanolamine, a plasticizer, a solubilizer, a pore-forming agent, and a flavoring agent into water under stirring.
In the present invention, the solid content of the API suspension is preferably 5 to 20%, more preferably 10 to 15%.
The invention mixes the film forming material with water to obtain the base film liquid.
In the invention, when the film-forming material is polyvinyl alcohol, the water is preferably hot water, and the temperature of the hot water is preferably 90-100 ℃, more preferably 90-95 ℃; when the film-forming material is not polyvinyl alcohol, the water is ambient temperature water (i.e., the water does not need to be heated nor cooled).
In the present invention, the second mixing is preferably stirring mixing; the stirring and mixing speed is preferably 100 to 300rpm, more preferably 150 to 250rpm, and even more preferably 200rpm; the second mixing time is preferably 1-2 h, more preferably 1.5h; the second mixing is particularly preferably by adding the film-forming material to the water under stirring.
The second mixed liquid component is cooled to room temperature to obtain a base film liquid; the cooling method is not particularly limited, and a cooling method well known to those skilled in the art, such as natural cooling, may be used.
In the present invention, the solid content of the base film liquid is preferably 5 to 10%, more preferably 6 to 9%, and even more preferably 7 to 8%.
After the API suspension and the base film liquid are obtained, the API suspension and the base film liquid are mixed for the third time, and the coating and the drying are carried out to obtain the eltrombopag ethanolamine oral-soluble film.
The volume ratio of the API suspension to the base film liquid is not particularly limited, so as to meet the requirement that the mass ratio of Ai Qubo Pa ethanolamine to the film forming material is 20-40: 20-40.
In the present invention, the third mixing is preferably stirring mixing; the stirring and mixing speed is preferably 100 to 300rpm, more preferably 150 to 250rpm, and even more preferably 200rpm; the time of the third mixing is preferably 1 to 2 hours, more preferably 1.5 hours.
After the third mixing, the invention preferably further comprises defoaming the mixed solution obtained by the third mixing to obtain the API-membrane solution. In the invention, the defoaming preferably comprises vacuumizing and defoaming and standing in sequence, wherein the vacuum degree of vacuumizing and defoaming is preferably-90 to-100 MPa, more preferably-90 to-95 MPa; the time for vacuumizing and defoaming is preferably 1-2 hours, more preferably 1.5 hours; the standing time is preferably 24-48 hours, more preferably 24-30 hours; the temperature of the defoaming is preferably room temperature.
The coating method is not particularly limited, and the eltrombopag ethanolamine oral solution film with the thickness of 0.06-0.17 mm can be obtained by adopting a coating mode which is well known to a person skilled in the art.
In the invention, the drying temperature is preferably 60-80 ℃, more preferably 65-75 ℃, and even more preferably 70 ℃; the total drying time is preferably 15 to 90 minutes, more preferably 30 to 80 minutes, and even more preferably 40 to 50 minutes. In the present invention, the drying preferably includes a first stage drying preferably including a first heat up and a first heat preservation drying, and a second stage drying preferably including a second heat up and a second heat preservation drying in order; the temperature rising rate of the first temperature rising and the second temperature rising is independently preferably 20-30 ℃/min, more preferably 20-25 ℃/min; the temperature of the first heat preservation and drying is preferably 60-80 ℃, more preferably 60-70 ℃, further preferably 60-65 ℃, and the time of the first heat preservation and drying is preferably 7.5-45 min, more preferably 10-20 min; the temperature of the second heat-preserving drying is preferably 60-80 ℃, more preferably 65-75 ℃, further preferably 70-75 ℃, and the time of the second heat-preserving drying is preferably 7.5-45 min, more preferably 25-30 min.
After the drying, the method preferably further comprises the step of cutting the obtained dried film to obtain the eltrombopag ethanolamine oral solution film, wherein the method is not particularly limited in the cutting, and the eltrombopag ethanolamine oral solution film with the length multiplied by the width= (3-3.5) cm multiplied by (2-2.5) cm can be obtained.
The invention provides an application of the eltrombopag ethanolamine oral dissolved film in the technical scheme or the eltrombopag ethanolamine oral dissolved film prepared by the preparation method in the technical scheme in preparing medicines for treating glucocorticoid-mediated diseases, immunoglobulin-mediated diseases or thrombocytopenia.
The technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
Ai Qubo dry basis components of the monoethanolamine orolysis film: 25% Ai Qubo Pa ethanolamine, 30% sodium alginate, 10% polyvinyl alcohol, 15% glycerol, 15% mannitol, 4% Tween 80, and 1% sucralose. Ai Qubo Pa ethanolamine D 90 Particle size is less than or equal to 10 mu m. The drug loading rate of Ai Qubo Pa ethanolamine oral solution film is 25%, the mass content of water is 3.62%, and the thickness is 0.08mm.
1) 3.20g Ai Qubo Pa ethanolamine, 1.92g glycerol, 1.92g lactose, 0.51g Tween 80 and 0.13g sucralose were added to 100mL purified water with stirring to obtain an API suspension, the stirring speed was 300rpm, and the total stirring time was 1h.
2) Adding 3.84g of sodium alginate and 1.28g of polyvinyl alcohol into 100mL of purified water at 90 ℃ while stirring, uniformly mixing, and cooling to room temperature to obtain a base membrane solution; the stirring speed was 300rpm and the total stirring time was 2 hours.
3) And (3) mixing the base membrane liquid and the API suspension for 2 hours under the condition of 300rpm and stirring, vacuumizing and defoaming for 2 hours under the condition of-90 MPa, and then standing for 24 hours under normal pressure to obtain the API-membrane liquid.
4) Coating the API-membrane liquid, heating to 65 ℃ at the speed of 25 ℃/min, then carrying out heat preservation and drying for 20min, heating to 70 ℃ at the speed of 25 ℃/min, then carrying out heat preservation and drying for 30min, and cutting (length multiplied by width=3 cm multiplied by 2 cm) to obtain the Ai Qubo Pa ethanolamine oral-soluble membrane. Ai Qubo Pa ethanolamine oral-dissolving film has smooth and flat appearance, the disintegration time is 41 seconds, and the disintegration speed of Ai Qubo Pa ethanolamine oral-dissolving film is high.
Example 2
The dry basis components of Ai Qubo Pa ethanolamine oral solution film include: 25% Ai Qubo Pa ethanolamine, 30% hypromellose, 10% polyvinyl alcohol, 14% PEG400, 18% mannitol, 2% poloxamer 188, and 1% sucralose. Ai Qubo Pa ethanolamine D 90 Particle size is less than or equal to 10 mu m. The drug loading rate of Ai Qubo Pa ethanolamine oral solution film is 25%, the mass content of water is 4.71%, and the thickness is 0.08mm.
1) Adding 100mL of purified water to 3.20g Ai Qubo Pa ethanolamine, 1.79g PEG400, 2.30g mannitol, 0.26g poloxamer 188 and 0.13g sucralose while stirring, and uniformly mixing to obtain an API suspension; the stirring speed was 300rpm and the total stirring time was 1h.
2) 3.84g of hypromellose and 1.28g of polyvinyl alcohol are added to 100mL of purified water at 90 ℃ while stirring, and the mixture is cooled to room temperature to obtain a base film liquid. The stirring speed was 300rpm and the total stirring time was 2 hours.
3) Mixing the base membrane liquid with the API suspension, stirring for 30min at the rotating speed of 300rpm, vacuumizing and defoaming for 2h under the condition of-90 MPa, and standing for 24h under the normal pressure to obtain the API-membrane liquid.
4) Coating the API-membrane liquid, heating from 0 ℃ to 65 ℃ at the speed of 25 ℃/min, then carrying out heat preservation and drying for 20min, heating from 0 ℃ to 70 ℃ at the speed of 25 ℃/min, then carrying out heat preservation and drying for 30min, and cutting (length multiplied by width=3 cm multiplied by 2 cm) to obtain the Ai Qubo Pa ethanolamine oral-soluble membrane. Ai Qubo Pa ethanolamine oral-dissolving film has smooth and flat appearance, the disintegration time is 30 seconds, and the disintegration speed of Ai Qubo Pa ethanolamine oral-dissolving film is high.
Example 3
Ai Qubo dry basis components of the monoethanolamine orolysis film: 25% Ai Qubo Pa ethanolamine, 20% polyvinyl alcohol, 20% hypromellose, 15% glycerol, 15% lactose, 4% vitamin E succinate, and 1% sucralose. MoxaTripopaman D 90 Particle size is less than or equal to 10 mu m. The drug loading rate of Ai Qubo Pa ethanolamine oral solution film is 25%, the mass content of water is 3.79%, and the thickness is 0.08mm.
1) 3.20g Ai Qubo Pa ethanolamine, 1.92g glycerol, 1.92g lactose, 0.51g vitamin E succinate, and 0.13g sucralose were added to 100mL purified water with stirring and mixed well to obtain an API suspension. The stirring speed was 300rpm and the total stirring time was 1h.
2) 2.56g of polyvinyl alcohol and 2.56g of hypromellose are added into purified water at 90 ℃ while stirring, and the mixture is cooled to room temperature to obtain a base film liquid. The stirring speed was 300rpm and the total stirring time was 2 hours.
3) Stirring the base membrane liquid and the API suspension for 2 hours at 3000rpm, vacuumizing and defoaming for 2 hours at-90 MPa, and standing for 24 hours at normal pressure to obtain the API-membrane liquid.
4) Coating the API-membrane liquid, heating from 0 ℃ to 65 ℃ at the speed of 25 ℃/min, then carrying out heat preservation and drying for 20min, heating from 0 ℃ to 70 ℃ at the speed of 25 ℃/min, then carrying out heat preservation and drying for 30min, and cutting (length multiplied by width=3 cm multiplied by 2 cm) to obtain the Ai Qubo Pa ethanolamine oral-soluble membrane. Ai Qubo Pa ethanolamine oral-dissolving film has smooth and flat appearance, the disintegration time is 32 seconds, and the disintegration speed of Ai Qubo Pa ethanolamine oral-dissolving film is high.
Example 4
The dry basis components of Ai Qubo Pa ethanolamine oral solution film include: 20% Ai Qubo Pa ethanolamine, 29% polyvinyl alcohol, 20% glycerol, 20% mannitol, 10% meglumine, 1% sucralose. Ai Qubo Pa ethanolamine D 90 Particle size is less than or equal to 10 mu m. The drug loading rate of Ai Qubo Pa ethanolamine oral solution film is 20%, the mass content of water is 4.26%, and the thickness is 0.17mm.
1) Adding 100mL of purified water to 3.20g Ai Qubo Pa ethanolamine, 3.20g mannitol, 3.20g glycerol and 1.60g meglumine while stirring, and uniformly mixing to obtain an API suspension; the stirring speed was 300rpm and the total stirring time was 1h.
2) 4.46g of polyvinyl alcohol was added to 100mL of purified water at 90℃with stirring, and the mixture was cooled to room temperature to obtain a base film liquid. The stirring speed was 300rpm and the total stirring time was 2 hours.
3) Mixing the base membrane liquid with the API suspension, stirring for 30min at the rotating speed of 300rpm, vacuumizing and defoaming for 2h under the condition of-90 MPa, and standing for 24h under the normal pressure to obtain the API-membrane liquid.
4) Coating the API-membrane liquid, heating from 0 ℃ to 65 ℃ at the speed of 25 ℃/min, then carrying out heat preservation and drying for 20min, heating from 0 ℃ to 70 ℃ at the speed of 25 ℃/min, then carrying out heat preservation and drying for 30min, and cutting (length multiplied by width=3 cm multiplied by 2 cm) to obtain the Ai Qubo Pa ethanolamine oral-soluble membrane. Ai Qubo Pa ethanolamine oral-dissolving film has smooth and flat appearance, the disintegration time is 60 seconds, and the disintegration speed of Ai Qubo Pa ethanolamine oral-dissolving film is faster.
Example 5
The dry basis components of Ai Qubo Pa ethanolamine oral solution film include: 20% Ai Qubo Pa ethanolamine, 40% polyvinyl alcohol, 10% polyethylene glycol, 5% mannitol, 20% poloxamer 188, 5% sucralose. Ai Qubo Pa ethanolamine D 90 Particle size is less than or equal to 10 mu m. The drug loading rate of Ai Qubo Pa ethanolamine oral solution film is 20%, the mass content of water is 5.11%, and the thickness is 0.12mm.
1) Adding 100mL of purified water into 3.20g Ai Qubo Pa ethanolamine, 6.40g mannitol, 1.60g glycerol and 3.20g poloxamer 188 while stirring, and uniformly mixing to obtain an API suspension; the stirring speed was 300rpm and the total stirring time was 1h.
2) 6.40g of polyvinyl alcohol was added to 100mL of purified water at 90℃with stirring, and the mixture was cooled to room temperature to obtain a base film liquid. The stirring speed was 300rpm and the total stirring time was 2 hours.
3) Mixing the base membrane liquid with the API suspension, stirring for 30min at the rotating speed of 300rpm, vacuumizing and defoaming for 2h under the condition of-90 MPa, and standing for 24h under the normal pressure to obtain the API-membrane liquid.
4) Coating the API-membrane liquid, heating from 0 ℃ to 65 ℃ at the speed of 25 ℃/min, then carrying out heat preservation and drying for 20min, heating from 0 ℃ to 70 ℃ at the speed of 25 ℃/min, then carrying out heat preservation and drying for 30min, and cutting (length multiplied by width=3 cm multiplied by 2 cm) to obtain the Ai Qubo Pa ethanolamine oral-soluble membrane. Ai Qubo Pa ethanolamine oral-dissolving film has smooth and flat appearance, the disintegration time is 45 seconds, and the disintegration speed of Ai Qubo Pa ethanolamine oral-dissolving film is high.
Example 6
The dry basis components of Ai Qubo Pa ethanolamine oral solution film include: 40% Ai Qubo Pa ethanolamine, 40% polyvinyl alcohol, 10% glycerol, 5% mannitol, 1% meglumine, 4% sucralose. Ai Qubo Pa ethanolamine D 90 Particle size is less than or equal to 10 mu m. The drug loading rate of Ai Qubo Pa ethanolamine oral solution film is 40%, the mass content of water is 3.98%, and the thickness is 0.06mm.
1) Adding 100mL of purified water to 3.20g Ai Qubo Pa ethanolamine, 0.40g mannitol, 0.80g glycerol and 0.10g meglumine while stirring, and uniformly mixing to obtain an API suspension; the stirring speed was 300rpm and the total stirring time was 1h.
2) 3.20g of polyvinyl alcohol was added to 100mL of purified water at 90℃with stirring, and the mixture was cooled to room temperature to obtain a base film liquid. The stirring speed was 300rpm and the total stirring time was 2 hours.
3) Mixing the base membrane liquid with the API suspension, stirring for 30min at the rotating speed of 300rpm, vacuumizing and defoaming for 2h under the condition of-90 MPa, and standing for 24h under the normal pressure to obtain the API-membrane liquid.
4) Coating the API-membrane liquid, heating from 0 ℃ to 65 ℃ at the speed of 25 ℃/min, then carrying out heat preservation and drying for 20min, heating from 0 ℃ to 70 ℃ at the speed of 25 ℃/min, then carrying out heat preservation and drying for 30min, and cutting (length multiplied by width=3 cm multiplied by 2 cm) to obtain the Ai Qubo Pa ethanolamine oral-soluble membrane. Ai Qubo Pa ethanolamine oral-dissolving film has smooth and flat appearance, the disintegration time is 57 seconds, and the disintegration speed of Ai Qubo Pa ethanolamine oral-dissolving film is high.
Comparative example 1
Ai Qubo Pa ethanolamine orosol film prepared according to the method of example 3 differs from example 3 only in that: vitamin E succinate was omitted.
Test example 1
Performance test of Ai Qubo pa ethanolamine oral films prepared in examples 1 to 6 and comparative example 1.
(1) Dissolution test: ai Qubo Pa ethanolamine orolysis membrane was dissolved in artificial saliva, followed by addition of pH=6.8 medium (containing 0.5wt% Tween 80); the dissolution method is a paddle method; the rotating speed is 50rpm when the rotating speed is less than 60min, and the rotating speed is 250rpm when the rotating speed is 60-70 min.
(2) Tensile strength and elongation at break test: and testing by using a tensile tester.
The dissolution, tensile strength and elongation of Ai Qubo Pa ethanolamine oral film were measured and are shown in Table 1.
Table 1 results of Performance test of Ai Qubo Pa ethanolamine oral solution films prepared in examples 1 to 6 and comparative example 1
As shown in Table 1, the cumulative dissolution rate of Ai Qubo Pa ethanolamine of the Ai Qubo Pa ethanolamine oral film provided by the invention can be more than or equal to 94% within 70min, and the dissolution rate of the bulk drug is high; the tensile strength is above 13.8MPa, the elongation at break is above 1.25%, and the Ai Qubo Pa ethanolamine oral film provided by the invention has the advantages of high dissolution rate of Ai Qubo Pa ethanolamine as a raw material, high tensile strength, high elongation at break and excellent mechanical property.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (10)
1. The Artemisia-bauhinia ethanolamine oral dissolved film comprises the following dry-based components in percentage by mass: ai Qubo Pa ethanolamine 20-40%, film forming material 20-40%, plasticizer 10-20%, pore-forming agent 5-20% and solubilizer 1-10%; the mass content of water in the eltrombopag ethanolamine oral dissolved film is 3-8%; d of the Ai Qubo Pa ethanolamine 90 Particle size is less than or equal to 10 mu m.
2. The eltrombopag ethanolamine oral film according to claim 1, wherein the eltrombopag ethanolamine oral film has a thickness of 0.06-0.17 mm, a length of 3-3.5 cm, and a width of 2-2.5 cm.
3. The eltrombopag ethanolamine orosol film according to claim 1 or 2, wherein the film-forming material comprises at least one of hypromellose, polyvinyl alcohol, maltodextrin, and sodium alginate.
4. The eltrombopag ethanolamine orosol film according to claim 1 or 2, wherein the plasticizer comprises at least one of glycerin, polyvinyl alcohol, and propylene glycol.
5. The eltrombopag ethanolamine orolysis membrane of claim 1 or 2, wherein the porogen comprises at least one of lactose, erythritol, and mannitol.
6. The eltrombopag ethanolamine orosol film according to claim 1 or 2, wherein the solubilizing agent comprises at least one of poloxamer 188, tween 80, sodium dodecyl sulfate, vitamin E succinate, and meglumine.
7. The eltrombopag ethanolamine oral film according to claim 1 or 2, wherein the composition of the eltrombopag ethanolamine oral film further comprises a flavoring agent of 5% or less in mass percent.
8. The preparation method of the eltrombopag ethanolamine oral film according to any one of claims 1 to 7, comprising the following steps:
(1) First mixing Ai Qubo Pa ethanolamine, a plasticizer, a solubilizer, a pore-forming agent and water to obtain an API suspension; when the components of the eltrombopag ethanolamine oral solution film do not contain one or more of plasticizer, pore-forming agent, solubilizer and flavoring agent, the corresponding raw materials are not added;
(2) Secondly mixing a film forming material with water to obtain a base film liquid;
(3) Thirdly mixing the API suspension with the base film liquid, and drying after coating to obtain an eltrombopag ethanolamine oral solution film;
the step (1) and the step (2) have no time sequence.
9. The method of claim 8, wherein the API suspension has a solids content of 5-20%; the solid content of the base film liquid is 5-10%;
the rotation speeds of the first mixing, the second mixing and the third mixing are independently 100-300 rpm, and the time is independently 1-2 h.
10. Use of an eltrombopag ethanolamine oral film according to any one of claims 1 to 7 or an eltrombopag ethanolamine oral film prepared by the preparation method according to any one of claims 8 to 9 in the preparation of a medicament for treating glucocorticoid-mediated diseases, immunoglobulin-mediated diseases or thrombocytopenia.
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| US20230022228A1 (en) * | 2019-12-06 | 2023-01-26 | Synthon B.V. | Pharmaceutical composition comprising eltrombopag bis(monoethanolamine) |
| CN115867351A (en) * | 2020-06-27 | 2023-03-28 | 劳拉斯实验室有限公司 | Oral cavity membrane of HIV medicine |
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| CN107595821A (en) * | 2017-11-13 | 2018-01-19 | 河南天晟泰丰医药科技有限公司 | A kind of gliclazide oral instant membrane and preparation method thereof |
| US20230022228A1 (en) * | 2019-12-06 | 2023-01-26 | Synthon B.V. | Pharmaceutical composition comprising eltrombopag bis(monoethanolamine) |
| CN115867351A (en) * | 2020-06-27 | 2023-03-28 | 劳拉斯实验室有限公司 | Oral cavity membrane of HIV medicine |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117281780A (en) * | 2023-11-24 | 2023-12-26 | 山东则正医药技术有限公司 | Airotopaolamine dry suspension and preparation method thereof |
| CN117281780B (en) * | 2023-11-24 | 2024-02-02 | 山东则正医药技术有限公司 | Airotopaolamine dry suspension and preparation method thereof |
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