CN118542852B - Sublingual film composition containing orally administered dexmedetomidine, and preparation method and application thereof - Google Patents
Sublingual film composition containing orally administered dexmedetomidine, and preparation method and application thereof Download PDFInfo
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- CN118542852B CN118542852B CN202411027840.7A CN202411027840A CN118542852B CN 118542852 B CN118542852 B CN 118542852B CN 202411027840 A CN202411027840 A CN 202411027840A CN 118542852 B CN118542852 B CN 118542852B
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- China
- Prior art keywords
- dexmedetomidine
- peo
- membrane composition
- sublingual
- sublingual membrane
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- 229960004253 dexmedetomidine Drugs 0.000 title claims abstract description 40
- HRLIOXLXPOHXTA-NSHDSACASA-N dexmedetomidine Chemical compound C1([C@@H](C)C=2C(=C(C)C=CC=2)C)=CN=C[N]1 HRLIOXLXPOHXTA-NSHDSACASA-N 0.000 title claims abstract description 40
- 239000000203 mixture Substances 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 239000012528 membrane Substances 0.000 claims abstract description 35
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 16
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 16
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 15
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol group Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000000463 material Substances 0.000 claims abstract description 11
- 229960002746 dexmedetomidine hydrochloride Drugs 0.000 claims abstract description 9
- VPNGEIHDPSLNMU-MERQFXBCSA-N dexmedetomidine hydrochloride Chemical compound Cl.C1([C@@H](C)C=2C(=C(C)C=CC=2)C)=CNC=N1 VPNGEIHDPSLNMU-MERQFXBCSA-N 0.000 claims abstract description 9
- 239000004014 plasticizer Substances 0.000 claims abstract description 8
- 239000000932 sedative agent Substances 0.000 claims abstract description 5
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims abstract description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 20
- 238000001035 drying Methods 0.000 claims description 7
- 239000011248 coating agent Substances 0.000 claims description 6
- 238000000576 coating method Methods 0.000 claims description 6
- 235000003599 food sweetener Nutrition 0.000 claims description 6
- 239000003765 sweetening agent Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000004376 Sucralose Substances 0.000 claims description 3
- 238000005520 cutting process Methods 0.000 claims description 3
- 239000003002 pH adjusting agent Substances 0.000 claims description 3
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 3
- 235000019408 sucralose Nutrition 0.000 claims description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- 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 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 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 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000004806 packaging method and process Methods 0.000 claims description 2
- -1 polyoxyethylene Polymers 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- 229940013618 stevioside Drugs 0.000 claims description 2
- 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 claims description 2
- 235000019202 steviosides Nutrition 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 230000008961 swelling Effects 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- 210000004379 membrane Anatomy 0.000 abstract description 25
- 239000003814 drug Substances 0.000 abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 5
- 230000009471 action Effects 0.000 abstract description 4
- 210000002200 mouth mucosa Anatomy 0.000 abstract description 4
- 238000010579 first pass effect Methods 0.000 abstract description 3
- 210000004185 liver Anatomy 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 230000001624 sedative effect Effects 0.000 abstract description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 20
- 238000001514 detection method Methods 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000007689 inspection Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000005452 bending Methods 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229960003943 hypromellose Drugs 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000004877 mucosa Anatomy 0.000 description 2
- 230000001603 reducing effect Effects 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000004368 Modified starch Substances 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 239000000384 adrenergic alpha-2 receptor agonist Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- DGLRDKLJZLEJCY-UHFFFAOYSA-L disodium hydrogenphosphate dodecahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].OP([O-])([O-])=O DGLRDKLJZLEJCY-UHFFFAOYSA-L 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 229940074928 isopropyl myristate Drugs 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 229920003169 water-soluble polymer Polymers 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
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A61P9/12—Antihypertensives
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Rheumatology (AREA)
- Cardiology (AREA)
- Pain & Pain Management (AREA)
- Heart & Thoracic Surgery (AREA)
- Anesthesiology (AREA)
- Hospice & Palliative Care (AREA)
- Otolaryngology (AREA)
- Inorganic Chemistry (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the field of pharmaceutical preparations, and in particular relates to a dexmedetomidine sublingual membrane composition containing oral administration, a preparation method and application thereof. The dexmedetomidine sublingual membrane composition comprises dexmedetomidine hydrochloride, a membrane forming material, a plasticizer and a pH regulator; the film forming materials are HPMC E15 and PEO; the plasticizer is glycerol; the pH regulator is citric acid and disodium hydrogen phosphate. The dexmedetomidine sublingual membrane composition provided by the invention can be rapidly absorbed by oral mucosa, achieves the purpose of rapid onset of action, can avoid the first pass effect of liver and improves the bioavailability of the drug. The sublingual membrane is orally taken without water, is convenient to administer, and is particularly suitable for sedative administration of various operations.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and in particular relates to a dexmedetomidine sublingual membrane composition containing oral administration, a preparation method and application thereof.
Background
Dexmedetomidine (Dexmedetomidine) is a potent alpha 2-adrenoceptor agonist with sedative, anxiolytic, analgesic, hypotensive, nausea and vomiting reducing effects. Dexmedetomidine is usually provided in the form of an injection, but when dexmedetomidine is infused simultaneously with blood or plasma, it may undergo pharmacodynamic interactions with certain components thereof, thereby affecting the processes of metabolism, distribution, excretion, etc. of the drug. Such interactions may lead to abnormally increased or decreased drug concentrations, thereby affecting the efficacy and safety of the drug. Thus, dexmedetomidine must not be infused through the same venous access as blood or plasma.
Sublingual membranes, also known as orolytic membranes, oral fast dissolving membranes, orodispersible membranes, etc., are a new drug delivery system. The active ingredients of chemical or traditional Chinese medicine extract with a certain dosage are fixed on a film sheet made of modified starch and colloid, and the size, shape and thickness of the film sheet are similar to those of a stamp. After the sublingual film is placed under the tongue, the medicine can be quickly dissolved and released in saliva without drinking water. This mode of administration has the following advantages: the onset of action is fast: the vascularization degree of the oral mucosa is high, no horny layer exists, and the permeability of the mucosa is high, so that the absorption speed and the acting speed of the medicine are faster compared with other administration routes. (2) high bioavailability: the medicine directly enters the systemic circulation after being absorbed by the oral mucosa, so that the first pass effect is avoided, and the mucosa adhesion administration prolongs the residence time of the medicine and improves the bioavailability. (3) high compliance: the sublingual film is easy to use, does not cause pain like injection, and is convenient to carry. This mode of administration has better patient compliance for children, the elderly and dysphagia patients. (4) high security: compared with liquid preparations, sublingual film preparations can improve the dosage accuracy, and each film is endowed with accurate medicine dosage so as to ensure the safety of the medication of patients.
Thus, the development of a dexmedetomidine sublingual membrane is advantageous for its rapid onset of action, high bioavailability, good patient compliance, providing new treatment options for specific patient populations.
Disclosure of Invention
To solve the above problems, a soluble film is provided comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, one or more water soluble polymers and optionally one or more pharmaceutically acceptable carriers. The film is formulated to release dexmedetomidine rapidly so that dexmedetomidine is available for transmucosal absorption to provide effective sedation to the patient within minutes.
In one aspect, the present invention provides a dexmedetomidine sublingual membrane composition comprising a film forming material, a plasticizer and a pH adjusting agent; the film forming materials are HPMC E15 and PEO; the plasticizer is glycerol; the pH regulator is citric acid and disodium hydrogen phosphate.
Specifically, the pharmaceutically acceptable salt is dexmedetomidine hydrochloride.
Preferably, the dexmedetomidine hydrochloride content is 0.1 [ mu ] g-10 [ mu ] g/mg, such as any concentration in any of 0.1 [ mu ] g, 0.2 [ mu ] g, 0.3 [ mu ] g, 0.4 [ mu ] g, 0.5 [ mu ] g, 0.6 [ mu ] g, 0.7 [ mu ] g, 0.8 [ mu ] g, 0.9 [ mu ] g, 1 [ mu ] g, 2 [ mu ] g, 3 [ mu ] g, 4 [ mu ] g, 5 [ mu ] g, 6 [ mu ] g, 7 [ mu ] g, 8 [ mu ] g, 9 [ mu ] g, 10 [ mu ] g and the range thereof.
Specifically, the mass ratio of HPMC E15 to PEO may be A, 1:1.ltoreq.A <1:2.
Further specifically, the mass ratio of HPMC E15 to PEO may be 1:1.
More specifically, the PEO is polyoxyethylene with the molecular weight of 10 ten thousand to 60 ten thousand; the PEO is one or more selected from PEO N10, PEO N80, PEO N750, PEO N3000 and PEO 205.
Still more particularly, the PEO is PEO N10 and PEO N80.
Preferably, the mass ratio of PEO N10 to PEO N80 can be 1:4 to 4:1, including but not limited to 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, and 4:1, and any ratio within these ratio ranges.
Further preferably, the mass ratio of PEO N10 to PEO N80 may be 1:2 to 1:3.
In particular, the film material may be present at any concentration within the range of 50% to 90%, such as 60%, 70%, 80%, 90%, and any concentration within the range of 60%, 70%, 80%, 90% by weight of the dexmedetomidine sublingual film composition.
Specifically, the dexmedetomidine sublingual membrane composition further includes a sweetener.
Preferably, the sweetener is selected from one or more of sucrose, stevioside, sucralose, xylitol, sorbitol, or mannitol.
Further preferably, the sweetener may be sucralose.
Specifically, the dexmedetomidine sublingual membrane composition further comprises a solvent; the solvent is one or more selected from water, ethanol, propylene glycol, polyethylene glycol, butanol, glyceryl triacetate, ethyl acetate, ethyl oleate, benzyl benzoate or isopropyl myristate.
Preferably, the solvent may be water.
In yet another aspect, the present invention provides the use of the dexmedetomidine sublingual membrane composition described previously in the manufacture of a sedative drug.
Specifically, the medicine also has various effects of resisting anxiety, easing pain, reducing blood pressure, relieving nausea and vomiting reaction and the like.
In yet another aspect, the invention provides a method for preparing the dexmedetomidine sublingual membrane composition, wherein the steps include mixing raw materials and auxiliary materials, swelling, defoaming, coating, drying, cutting and packaging.
Specifically, the defoaming adopts a standing method to remove bubbles.
Specifically, the coating thickness may be 500-900 μm.
Further specifically, the coating thickness may be 600-800 μm.
Preferably, the application thickness may be 700 μm.
In particular, the drying temperature may be 40-60 ℃.
Further specifically, the drying temperature may be 45-55 ℃.
Preferably, the drying temperature may be 50 ℃.
Specifically, the cutting size can be 2-3cm long and 1-2cm wide.
Preferably, the cut size may be 1cm×2cm.
The invention has the technical effects that:
(1) The dexmedetomidine sublingual membrane prepared by the method of the invention adopts HPMC and PEO to control better adhesiveness and proper disintegration time, can be rapidly absorbed by oral mucosa, and achieves the purpose of rapid onset of action; meanwhile, the damage of the oral gastrointestinal tract and the first pass effect of the liver can be avoided, and the bioavailability of the medicine is improved.
(2) The dexmedetomidine sublingual membrane prepared by the method does not need water for oral administration, and is particularly suitable for serving as a preoperative sedative drug.
(3) The dexmedetomidine sublingual membrane prepared by the method has good folding endurance, and no obvious defect in bending, wherein the group 20 is not broken.
(4) The dexmedetomidine sublingual membrane prepared by the method has good adhesion, does not fall off after more than 8 minutes, and is dissolved.
(5) The dexmedetomidine sublingual membrane prepared by the method has strong stability, and the stability is still kept in a 40 ℃ constant temperature and humidity box for 3 months.
Drawings
FIG. 1 shows the result of the histopathological examination of example 1, showing no significant histopathological changes in the left cheek pouch (24 hours after the last administration, test sample group).
FIG. 2 is the result of the histopathological examination of example 1, showing no significant histopathological changes in the left cheek pouch (end of recovery period, test panel).
Detailed Description
The present invention will be described in further detail with reference to the following examples, which are not intended to limit the present invention, but are merely illustrative of the present invention. The experimental methods used in the following examples are not specifically described, but the experimental methods in which specific conditions are not specified in the examples are generally carried out under conventional conditions, and the materials, reagents, etc. used in the following examples are commercially available unless otherwise specified.
Example 1
1.1 Preparation method
A method for preparing a dexmedetomidine sublingual membrane composition having the formulation shown in table 1:
Table 1 formulation of example 1
The preparation process comprises the following steps: adding a film forming material into water, magnetically stirring to uniformly disperse and fully swell, adding an active ingredient, a plasticizer, a pH regulator and a sweetener, fully stirring to uniformly disperse, removing bubbles by adopting a standing method after the system is uniform, coating a film on a coating machine according to the thickness of 700 mu m, and drying at 50 ℃ to obtain a dexmedetomidine hydrochloride sublingual film, wherein the length of the dexmedetomidine hydrochloride sublingual film is 2-3cm, and the width of the dexmedetomidine sublingual film is 1-2cm. The film is preferably cut to a size of 1cm by 2cm.
1.2 Property and disintegration time detection
The detection method comprises the following steps: the four parts of the "chinese pharmacopoeia" of 2020 edition have no relevant regulations of sublingual film, and thus are measured according to the disintegration time limit examination method (general rule 0921) under the four tablet items of the "chinese pharmacopoeia" of 2020 edition. 6 films of 1cm x 2cm are taken and placed into 6 baskets respectively, and the time counting is started when the films are contacted with water, and the disintegration time of each film is recorded.
The detection results are shown in Table 2:
TABLE 2
1.3 Content uniformity detection
The content uniformity inspection method (general rule 0941) under the four characteristic inspection method item of the edition 2020 of Chinese pharmacopoeia is adopted for inspection.
Preparation of a control solution: taking a proper amount of dexmedetomidine hydrochloride reference substance, adding 10% methanol for dissolution, quantitatively diluting to a solution of about 4 mug/ml, and shaking uniformly.
Preparation of test solution: taking 10 pieces of dexmedetomidine hydrochloride sublingual membrane, dissolving with 10% methanol and diluting into a solution with the concentration equivalent to that of a control.
Assay: octadecylsilane chemically bonded silica is used as a filler; taking phosphate buffer solution-methanol (30:70) with pH value of 7.8 as a mobile phase; the detection wavelength was 220nm. Precisely measuring the sample solution and the reference substance solution, respectively injecting into a liquid chromatograph, and recording the chromatograms. Calculated as peak area according to the external standard method.
10 Pieces of the dexmedomidine hydrochloride sublingual films prepared in example 1 were taken, a test solution was prepared according to the method described above for "preparation of test solution", and the labeling content of each film was calculated by measuring according to the method described above for "measurement method".
Detection result: the labeled content of each film was 98.56%; the content uniformity (A+2.2S < 20.0) meets the requirement.
1.4 Fold resistance: the 10 groups are folded without breaking (the front and back 90 degrees are folded into one group), and whether the film has defects or cracks is observed;
detection result: group 20 did not break and the bending was free of significant defects.
1.5, Adhesiveness: after rinsing with water, the film was placed under the tongue, and the film adhesion under the tongue and dissolution time (foreign body sensation disappearance time) were recorded, and the detection result was: no falling off is caused after 8min, and the film is melted.
1.6 Stability
The product of example 1 was placed in a 40℃constant temperature and humidity cabinet for 3 months, and the stability of the product was examined using the content, the related substances and the like as main examination indexes, and the 0d, 1 month, 2 months and 3 months were examined respectively. The detection method comprises the following steps: the detection was carried out by a high performance liquid chromatography system with a column of Ultimate XB-C18 (5 μm, 4.6X1250 mm), mobile phase A of 5% triethylamine (pH adjusted to 6.7 with phosphoric acid) and mobile phase B of acetonitrile at the detection wavelength: 220nm. The detection results are shown in Table 3.
TABLE 3 Table 3
1.7 Non-clinical local Security
Sublingual films prepared according to the method of example 1 were used as test groups, respectively, with 0.9% sodium chloride injection as a negative control group, golden yellow mice (SPF grade, breeding unit: beijing Vitolihua laboratory animal technologies Co., ltd.) were administered 1 time per day in cheek sachets, and the irritation to the administration site and reversibility after stimulation were observed after administration for 7 days, and the results are shown in Table 4:
TABLE 4 Table 4
Example 2
2.1 Preparation method
A method for preparing a dexmedetomidine sublingual membrane composition having the formulation shown in table 5:
table 5 formulation of example 2
The preparation procedure is as in example 1.
2.2 Property and disintegration time detection
The detection method is the same as in example 1.
The detection results are shown in Table 6:
TABLE 6
2.3 Content uniformity detection
The detection method is the same as in example 1.
Detection result: the labeled content of each film was 96.68%; the content uniformity (A+2.2S < 20.0) meets the requirement.
The compositions of example 2 were comparable to example 1 in folding endurance, adhesion, stability and non-clinical local safety.
Comparative example 1
HPMC E15 (hypromellose E15) in example 1 was replaced with equal amounts of HPMC E4M, HPMC e15+peo (hypromellose e15+polyoxyethylene), respectively. Film forming properties and disintegration time were measured and the measurement results are shown in table 7.
The film forming performance detection method comprises the following steps: (1) hand drying, direct touch; (2) The two hands hold the two ends of the membrane and fold and stretch under the parallel condition.
TABLE 7
Comparative example 2
The pH adjusting agents citric acid and disodium hydrogen phosphate dodecahydrate in example 1 were replaced with equal amounts of citric acid and sodium citrate, respectively. The pH adjustment result and the impurity condition were examined, and the results are shown in Table 8.
TABLE 8
Comparative example 3
The plasticizer glycerol in example 1 was replaced with the same amount of PEG400, and the film forming performance was measured, and the measurement results are shown in Table 9.
TABLE 9
Comparative example 4
HPMC in example 1: peo=1: 1 are respectively adjusted to HPMC: peo=1.5: 1. HPMC: peo=1: 2, film forming property, folding endurance and adhesion were measured respectively, and the measurement results are shown in Table 10.
Table 10
Conclusion of experiment: from the film forming performance point of view, the ratio of HPMC to PEO is 1:1 is the optimum ratio.
Claims (8)
1. A dexmedetomidine sublingual membrane composition, wherein the dexmedetomidine sublingual membrane composition comprises dexmedetomidine or a pharmaceutically acceptable salt thereof, a film forming material, a plasticizer and a pH adjusting agent; the film forming materials are HPMC E15 and PEO; the plasticizer is glycerol; the pH regulator is citric acid and disodium hydrogen phosphate;
The mass ratio of the HPMC E15 to the PEO is A, wherein A is more than or equal to 1:1 and less than or equal to 1:2;
the molecular weight of PEO is 10 ten thousand-60 ten thousand polyoxyethylene.
2. The dexmedetomidine sublingual membrane composition of claim 1, it is characterized in that the method comprises the steps of, the pharmaceutical acceptable the salt is dexmedetomidine hydrochloride; the dexmedetomidine hydrochloride content is 0.1-10 mug/mg.
3. The dexmedetomidine sublingual membrane composition of claim 2, wherein the PEO is selected from one or more of PEO N10, PEO N80, PEO N750, PEO N3000, PEO 205.
4. The dexmedetomidine sublingual membrane composition of claim 3 wherein the PEO is PEO N10 and PEO N80; the mass ratio of PEO N10 to PEO N80 is 1:4-4:1.
5. The dexmedetomidine sublingual membrane composition of any one of claims 1-4, wherein the dexmedetomidine sublingual membrane composition further comprises a sweetener.
6. The dexmedetomidine sublingual membrane composition of claim 5, wherein the sweetener is selected from one or more of sucrose, stevioside, sucralose, xylitol, sorbitol, or mannitol.
7. Use of a dexmedetomidine sublingual membrane composition as defined in any one of claims 1-6 in the manufacture of a sedative drug.
8. A process for the preparation of a dexmedetomidine sublingual membrane composition as claimed in any one of claims 1-6 wherein the preparation steps include mixing of the raw and auxiliary materials, swelling, defoaming, coating, drying, cutting and packaging.
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| WO2010132882A2 (en) * | 2009-05-15 | 2010-11-18 | Recro Pharma, Inc. | Sublingual dexmedetomidine compositions and methods of use thereof |
| CN112888431A (en) * | 2018-06-27 | 2021-06-01 | 比奥克斯塞尔医疗股份有限公司 | Dexmedetomidine-containing film preparation and method for producing the same |
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| WO2010132882A2 (en) * | 2009-05-15 | 2010-11-18 | Recro Pharma, Inc. | Sublingual dexmedetomidine compositions and methods of use thereof |
| CN112888431A (en) * | 2018-06-27 | 2021-06-01 | 比奥克斯塞尔医疗股份有限公司 | Dexmedetomidine-containing film preparation and method for producing the same |
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