LV10383B - Transdermal therapeutic system and method for producing thereof - Google Patents

Transdermal therapeutic system and method for producing thereof Download PDF

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Publication number
LV10383B
LV10383B LVP-93-1012A LV931012A LV10383B LV 10383 B LV10383 B LV 10383B LV 931012 A LV931012 A LV 931012A LV 10383 B LV10383 B LV 10383B
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Latvia
Prior art keywords
therapeutic system
transdermal therapeutic
acid
esters
weight
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LVP-93-1012A
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English (en)
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LV10383A (lv
Inventor
Hille Thomas
Hoffmann Hans-Rainer
Huber Hans-Joachim
Knoch Axel
Schneider Gerhard
Stanislaus Fritz
Original Assignee
Lohmann Therapie Syst Lts
Klinge Co Chem Pharm Fab
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Application filed by Lohmann Therapie Syst Lts, Klinge Co Chem Pharm Fab filed Critical Lohmann Therapie Syst Lts
Publication of LV10383A publication Critical patent/LV10383A/lv
Publication of LV10383B publication Critical patent/LV10383B/lv

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    • 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
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • 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
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • 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
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Psychiatry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hospice & Palliative Care (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Materials For Medical Uses (AREA)
  • Media Introduction/Drainage Providing Device (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Saccharide Compounds (AREA)
  • Steroid Compounds (AREA)

Description

LV 10383 TPAHCflEPMAnbHAfl ΤΕΡΑΠΕΒΤΙ/IHECKAfl CMCTEMA H CnOCOE EĒ ΠΟΠΥΗΕΗΜΗ
OnMCaHMe Μ3θ6ρθΤΘΗΜΑ Μ3θ6ρΘΤθΗΜΘ KacaeTca TpaHCflepManbHoii TepaneBTunecKOM oiCTeMbi, KOTopaa COflep>Km φΜ300ΤΜΓΜΜΗ B ΚείΗΘΟΤΒΘ aKTMBHOM ΚΟΜΠΟΗΘΗΤΝ, II ΟΠΟΟΟβθ θθ ΠΟΠγΗΘΗΜΒ.
Mcnonb30BaHne $M30CTMrMMHa nna πθηθημη 6οπθ3Ημ AnbupcaiiMepa onticaHO b nnTepaType, πρμηθμ αθμοτβμθ BemecTBa ομθημβθθτοα pa3nnMH0 pa3JiMHHbiMM aBTopavin. TaK, KaK 3tot anKanonfl oSnaflaeT bucokum θφφθκτοΜ nepBoro προμοχοχαθημη /first pass effect/ -6nopacnpejqenfleMOCTb Φμ300τμγμμη8 ripu ββθαθημμμ nepe3 ροτ οοοτθβπηθτ 5%, - to ΟΤΚΠΟΗΘΗΜΒ pe3ynbTaTOB 06bflCHflK)TCfl BapnaHTaMU ΠρΜΜΘΗΘΗΜΒ. B Bbino>KeHHOM 3aaBKe ΦΡΓ flE-OS N 3528979 onncaH οοοτθβ, KOTopbiPi, Happfly c φΜ300ΤΜΓΜΜΗ0Μ ΟΟΑθρΧΜΤ Kap60H0Byi0 KMCflOTy CO CpeflHeM ΑΠΜΗΟίί ΜΘΠΜ; 9T0T COCTaB ΜΟΧΘΤ 6biTb ηθηθοθη Ha 6mht, npoKnajqKy nnn KOMnpecc, KOTopbie 3aKpenneHbi c noMombio πθρθββ3κμ. 3tOT cnocoč ΓφΜΜΘΗΘΗΜΑ Ηθ ΠρθΑΟΤΘΒΠΒΘΤ ΟΟβοΡί TepaneBTMHeCKyiO CMCTGMy, nna κοτοροΡί npeAycMaTpMBaeTCH, hto 6aHflax/6mht/, KOMnpecc μπμ npoKnanKa CHa6xeHbi pe3epByapHbiM BHyTpeHHMM ΟΠΟΘΜ, HenpOHMUaeMOM 3ailļMTHO& ΠθρφορΜρΟΒΘΗΗΟΡί ΠΠΘΗΚΟΡί ΜΠΜ HenpoHnuaeMoPi 3atnnTHoPi φοπΒΓοΡί, a MexAy pe3epByapoM μ κοχθΡι HaHOcmcB ηθ ormcaHHafl paHee flnφφy3^10HHay^ ynpaBnaioLLiaH MeMčpaHa. Hm ΑΜφφν3Μ0ΗΗ3Β ynpaBnaiomaa MeM6paHa, m 3animHbie ππ§ηκμ ηθ 6binn onncaHbi paHbiue. KapāoHOBbie KMcnoTbi cneqnanbHO yKa3aHbi Kax θκτμβηοθ TpaHcnopTHoe CBH3yiomee cpencTBO απβ προημκηοβθημβ neKapcTBa nepe3 KOxy, TaK KaK HHane Henb3a 6bino 6bi o6o3HaHMTb θτο προημκηοβθημθ nepe3 κοχηνΡι 6apbep. θτο
BblCKa3blBaHHe Ηθ aBnaeTCa HayHHO OāOCHOBaHHbIM. B πθτθητθ ΦΡΓ flE - PS N 36 06 892 oriMcaHO peTapnaMMOHHoe πρμμθηθημθ φΐ1300ΤΜΓΜ11Η3 M flpyrMX βΜΟΠΟΓΜΗΘΟΚΜ ΘΚΤΜΒΗΝΧ ΒΘΙΙΙΘΟΤΒ, ΚΟΤΟρΟΘ ΜΟΧΘΤ OCymeCTBnflTbCfl TpaHCflepManbHO /nepe3 κοxy/. CneuiianbHaa peiļeirn/pa ηθ pacKpbiTa, a HanpoTMB, μμθθτοη ccbinKa Ha yxe onncaHHyio peuemypy /πθτθητ CUJA US - PS N 3.921.363/. 2
Hapafly c BecbMa HeonpepeneHHbiMM npiiMepaMii μοποπηθημβ TpaHcpepManbHoii TepaneBTMHecKoii cncTeMbi hh b opHOii M3 o6enx BbiuieynoMBHyrbix Bbino>KeHHbix 3a«BOK He yKa3biBaeTca Ha HecTa6nnbHOCTb Φμβοοτμγμμηθ, ο κοτοροίί yxe 6bino paBHO Μ3βθοτηο Eber W., Iharmaz. Ztg. 3Z, 483 /1888/;
Herrig F., Mayer A., Mh. Chem. 18,379 /1897/;
Herzig F., Lieb H., TaM >κθ 39,285 /1918/;
Solvey A.A., T. Chem Soc. (London) 101, 978 /1912/.
HecTa6nnbH0CTb BcnepcTBiie oneHb 6bicTporo pa3noxceHMB ycTaHaBnnBaeT y3Kne rpaHMUbi pna ncnonb30BaHHH Φμ300τμγμμη8 b cķapMaueBTMKe. 3aaaHeii Μ3ο6ρθτθημβ noaTOMy ββπβθτοβ πρμγοτοβπθημθ φιιβοσπιπνιιΐΗβ μπμ φ3ρΜ314ΘΒΤΜΗΘ0ΚΜ ΠθρβΗΟΟΙΜΗΧ ΟΟΠβίί φΜ300ΤΜΓΜΜΗ3 Β φορΜβ TpaHCflepMaJlbHOM TepaneBTMHecKoii cnoreMbi, KOTopaa nepee 24 naca KomporiwpyeMO OTflaēT φιιβοσπίΓΜΜΗ μπμ ero φ3ρΜ3ΜθΒΤΜΗβοκΜ nepeHociiMyio conb ii rapaHTiipyeT, ητο φιΐ3οσπΐΓΜΜΗ bo BpeMa χρβΗΘΗΜΒ πορΓοτοΒΠβΗΗοίί TpaHCflepManbHOM TepaneBTMHecKOM cncTeMbi ηθ 6ypeT 3HaHMTenbHO pa3naraTbc«.
PemeHne eapanu ocymecTBnfleTC« ānaropapa TOMy, ητο Φιι30οτίιγμιιη, no KpaiiHeii Mepe, 25%-m pacTBopaiOT b pacTBopmene ιιπιι CMecii pacTBopmeneii, KOTopbie florDKHbi 6biTb φΜ3ΜΟΠΟΓΜΗΘΟΚΜ ΠθρθΗΟΟΙΜΜΜΙΙ C ΤΘΜ, HTOdbl CHMTaTb, ΗΤΟ ΗΘ TOnbKO φΐ130σΠ1ΓΜΜΗ, HO ΤβΙΟΚΘ μ pacTBopiiTenb MnrpiipyeT nepe3 rpaHimy. Θτοτ pacTBop μοχθτ 6biTb npn noMomii paBneHiiB, Kax HanpiiMep, omicaHO b βηποχθηηομ 3a«BKe ΦΡΓ flE - OS N 36 29 304, HaHeceH Ha TeKCTiinbHyio 3aroTOBKy, pacnonaraK)myioc8 Ha μθτρμμθ, KOTopaa npepBapHTenbHO CHa6xeHa aKTMBHbiM HenpoHiiLļaeMbiM, b cnynae ΗθοδχοριίΜοοτιι, OTflenaeMbiM 3amnTHbiM οποθμ. Β 38κπιοηθηιιθ TeKCTnnbHyto 3aroTOBKy c ηθηθοθηημμ pacTBopoM m MaTpnqy noKpbiBaiOT npeflBapMTenbHO noflroTOBneHHbiM, TaioKe HenpoHkmaeMbiM fl/ia θκτμβηογο BeuuecTBa noKpoBHbiM cnoeM. C noMOLUbio cneuiianbHoro uiTaHLieBanbHoro MHCTpyMeHTa, noBepxHOCTb κοτοροΓΟ Kpyrnaa m bbho SonbLue, ηθμ noBepxHOCTb 3aroTOBKM M3 ηθτιοηογο MaTepHana, ocymecTBnfleTCH Bbipy6Ka. B 33κπιοηθημθ penaeTCfl peujeTHaTaa ceTKa Ha CBo5oflHbix οτ θκτμβηογο BemecTBa Kpaax. Θτοτ cnocoā, b npMHLiiine, Μ3βθοτθη m omicaH β βνποχθηηομ 3aaBKe ΦΡΓ flE - OS N 36 29 304. OflHaKo, b BbiweyKa3aHHon βνποχθηηομ 3aaBKe β κθηθοτβθ BeiuecTBa-npMMepa cny>Km HiiKOTHHOBoe οοηοββημθ. Tax xax ημκοτμηοβοθ οοηοβθημθ npH κομη3τηομ TeMnepaType >κμπκοθ, θτοτ cnocoā ηθ μο>κθτ ābiTb aflanTiipoBaH προοτο. HanpoTMB, φΐ1300ΤΜΓΜΜΗ Ρ0Π>ΚΘΗ BBOflHTbCH BblCOKOnpOLļeHTHblM, a 11ΜΘΗΗΟ 25%-HblM B paCTBOpe, T3K ΚβΚ, χοτα iiHflMBMflyanbHoe po3npoBaHne nopoiui<oo6pa3Hbix κομποοηθητ m pacnpocTpaHeHO b τθχηοπογιμ TBepflbix neKapcTBeHHbix φορΜ, οπηθκο β τθχηοπογμμ nonyTBepflbix neKapcTBGHHbix φορΜ oho aāconiOTHO ηθμ3ΒΘ0τηο, noTOMy, ητο stot Bonpoc jqo cnx πορ ηθ οτοβπ. Οαηοβρθμθηηο pacTBOpmenb αοπχθη yflOBneTBop^Tb eujē TpēM Ba>KHeiiiunM TpečoBaHHBM: - oh ne floroiceH pa3naraTb BbicoKo HecTaāmībHbiti Φμ300τμγμιιη; - OH ΑΟΠΧΘΗ He Bbl3blBaTb ΗΗΚΒΚΙ1Χ COMHeHMM C TOHK11 3peHMH φΐ13110Π0ΓΜΙΐ; - oh florDKeH očecneHMBaTb, HToābi Φμ30οτμγμμη χοροιυο pacTBOpaioiuMiicfl bo BpeMB ηρΐΙΓΟΤΟΒΠΘΗΙΙΗ ClICTeMbl, BO ΒρθΜΒ XpaHeHHB, OflHaKO, pacTBopancB 6bl KpaflHe He3HaHl1TenbH0. 3 LV 10383
Kap6oHOBbie KucnoTbi, KOTOpbie copepjKaT 6onee 10 btomob yrnepofla, γροπΘΤΒορπιοτ Ha3BaHHblM ΤρΘβΟΒΘΗΜΠΜ. ΠρΜ ΟΜΘΙΙΙΘΗΜΜ φΗ30σΤΜΓΜΜΗ3 C 3ΤΜΜΜ ΟΟΘΑΜΗΘΗΜΗΜΜ ΠρΟΜΟΧΟΑΜΤ κβκ noBbiiueHMe pacTBopnMOCTM, τθκ n o6pa30BaHne conen. npnHunnuanbHO, οαη3κο, hto TaKne 33γοτοβκμ npn κομηθτηομ TeMnepaType πβππιοτοπ χμρκμμμ.
PacTBopuMOCTb ānonorunecKU aīcniBHoro eemecTBa b MaTpnue ποημχθηθ /b pe3ynbTaTe ηθγο 6ypeT ροοτΜΓΗγτο AOCTaTOHHoe βμρθπθημθ/ Snaropapn TOMy, hto b Μβτρηργ ββθαθηβ BbicoKan ponn 6a3MCHoro nonuMepa, HanpnMep, cononMMepM3aT Κ3τμοηηογο xapaicrepa Ha ΟΟΗΟΒΘ ρΜΜΘΤΗΠ3ΜΗΗ03ΤΗΠΜΘΤ3ΚρΜΠ3Τ3 Μ ρργΓΜΧ HeMTpanbHblX θφηρΟΒ ΜΘΤβΚρΜΠΟΒΟΡί KMcnoTbi. B pe3yribTaTe HaHeceHMH MaTpnpbi προηοχορητ kmc/iotho - ocHOBHan peaKLļMfl Mexpy
KapāOHOBOii KMCHOTOM M OCHOBHbIM ΠΟΠΜΜβρΟΜ, ΒΟΠΘρσΓΒΜΘ ΗΘΓΟ 0γΐ11Θ0ΤΒΘΗΗ0 ΠΟΗΜΧβΘΤΟΠ pacTBopuMOCTb θκτμβηογο BemecTBa.
Ha ocHOBaHMM paHHbix peiļenTypHbix npuMepoe μοχθτ 6biTb noKa3aHO, hto cKopocTb BbipeneHna υβθπμηηβθθτοη c B03pacTaHkieM ροπή οοηοβηογο nonuMepa b MaTpnpe. Οχθμθτμηθοκοθ ποοτροθΗΜθ cncTeMbi μοχθτ 6biTb 6onee peTanbHO ποαοηθηο c noMOiiļbio npnnaraeMbix οχθμ.
Hapy>KHbiM cnon /4/ μοχθτ cocTonTb m anacTMHHoro μπμ HeanacTMHHoro MaTepnana m MMeTb opuH nnn HecKonbKO οποθβ. MaTepnanbi, KOTOpbie MoryT 6biTb npuMeHeHbi pnn ero ιι3γοτοβπθημ51, 3to ποπμμθρηνθ BemecTBa, τθκμθ Kax, HanpnMep, ποπμθτμπθη, nonnnponnneH, Π0ΠΜ3ΤΜΠΘΗ·ΤΘρΘφΤ3Π3Τ, ΠΟΠΜΘΜΜρ. Β Κ3ΗΘΟΤΒΘ ΡΡΥΓΜΧ ΜΘΤΘρΜΘΠΟΒ ΜΟΓγΤ TaiOKe ncnonb30BaTbca MeTannunecKue ππθηκμ, Taxne xax amoMMHMeBan φoπbΓa, προοτο φoπbΓa μπμ χθ φoπbΓaļ noKpbiTaa ποπμμθρηημ cy6cTaTOM /β ποοπθαηθμ cnynae /5//. Μοιγτ πρμμθηγπϊοπ TaioKe η TeKCTunbHbie noBepxHOCTHbie o6pa30BaHna, ecnn cocTaBHbie nacTM pe3epeyapa βοπθαοτβμθ ηχ φη3ΜΗθοκηχ οοο6θηηοοτθμ ηθ MoryT npoxopnTb nepe3 TeKCTMnbHbin MaTepnan. y Hanāonee npepnoHTMTenbHon φορΜΗ μοποπηθημπ ποκρνβηομ οποίί /4/ coctomt m3 KOM6nHnpoBaHHoro MaTepnana, KOTopbin oāecnennBaeT npoHHOCTb naMMHaTa n cnyxnT SapbepoM προτηΒ noTepb cocTaBHbix nacTen naMMHaTa. Hapnpy c stum pnn sthx penen npnropHbi TaioKe ππθηκμ, nonyneHHbie ηθπνπθημθμ θπιομμημπ nnn KOMČnHnpoBaHHbie ππθηκμ. K ΠΟΚρΟΒΗΟΜγ CnOIO/4/ npMMbIKaeT MaTpMUa/1/. Bo ΒρβΜΗ ΗΘΤΜρΗ3ρί13ΤΗΡΗΘΒΗ0Γ0 BblflepXMBaHMH /χρ3ΗΘΗΜΠ/ φΜ300ΤΜΓΜΜΗ ΠβρβΧΟρΜΤ Μ3 χρ3ΗΜΠΜ1113 6ΜΟΠΟΓΜΗΘΟΚΜ ΘΚΤΜΒΗΟΓΟ βθιαθοτβθ /2/ β Μβτρηργ /1/ μ HacbiipaeT eē, t3kmm o6pa30M MaTpnpa npeBpaipaeTcn β pe3epByapHbiM cnon. MaTpnLļa o6napaeTTaKMM cbomctbom, κοτοροθ očecneHMBaeT CBH3aHHOCTb CMCTeMbi. MaTpMLļa coctomt M3 οοηοβηογο nonnMepa μ, β cnynae ΗΘΟθχΟΑΜΜΟΟΤΜ, o6biHHbix poāaBOK. Bbičop οοηοβηογο nonMMepa copMeHTMpoBaH Ha χμμμηθοκμθ μ Φμ3μηθοκμθ CBOMCTBa φΜ300ΤΜΓΜΜΗ3. Β ΚΘΗΘΟΤΒΘ npMMepa MOryT 6blTb Ha3BaHbl CneAyKDUļHe nonMMepbi: KayHyKonoAo6Hbie, ομητθτμηθοκμθ γομο-, cononMMepbi μπμ 6noK-nonMMepbi, 3φηρ nonnaKpnnoBon kmchotu m ero cononMMepbi. KaK npaBMno, penb μοχθτ ματμ ο Bcex nonMMepax, KOTOpbie Moryr npMMeHHTbcn πρη μ3γοτοβπθημμ βπ3κμχ κπθθβ. Ohm φΜ3ΜΟΠΟΓΜΗΘΟΚΜ ΗΘ ΑΟΠΧΗΗ Bbl3blBaTb OnaceHMM Μ Ηβ ponXHbl pa3naraTb ΦΜ300ΤΜΓΜΜΗ. Hanāonee npepnoHTMTenbHbiMM πβππιοτοπ τθκμθ nonnMepbi, KOTOpbie πβππιοτοπ 6ποκ-cononMMepaMM Ha 6a3e CTMpona m 1,3-pMeHa, a TaioKe ποπμμ3ο6υτμπθημ μπμ ποπμμθρν Ha 6a3e aKpnnaTa μ/μπμ MeTaKpnnaTa. V\z nncna 6ποκ-οοποπμμθροβ Ha 6a3e CTMpona n 1,3-pMeHa HaMāonee npMropHbiMM πβππιοτοη πμηθμημθ CTMpon-M3onpeH-6noKCononMMepbi. 4 B KanecTBe ποπμμθροβ ηθ οοηοβθ aKpunaTa HanSonee npeAnoHTMTenbHbiMM 6ynyT aKpunai-cononuMepbi 2-3TMn-reKcnn-aKpMnaTa, BMHMnaqeTaTa μ aKpMAOBon KncnoTbi c nnn 6e3 TmaH-xenaT-30npa. B KanecTBe MeiaKpunaTOB npeflnoHTUTenbHbiMM ηβπακηόα cononMMepbi Ha OCHOBe ΑΜΜβΤΜΠ-3ΜΜΗ0-3ΤΜΠ-ΜβΤ3ΙφΜΠ3Τ3 M TenpanbHblX θφΜρΟΒ ΜβΤβΚρΜΠΟΒΟΜ KMCJlOTbl. B KanecTBe οπο>κηογο 30npa γμαρμροβθηηομ κβΗΜφοπΜ Hanāonee npenMymecTBeHHoe ΠΡΚΜΘΗΘΗΜΘ HaXOflaT, B OCOāeHHOCTM, ΜβΤΜΠΟΒΜΜ - M ΓΠΜΑβρΜΗΟΒΝΜ 3φΜρΜ. Τμπ B03M0)KHbix floSaBOK 33bmcmt οτ Mcnonb3yeMoro nomiMepa μ 6μοπογμηθοκμ aKTMBHoro BemecTBa. B οοοτβθτοτβμμ c μχ φνΗκυίΜηΜΜ 3tm floāaBKM noflpa3flenyiioTCB Ha cneny(omne: ηηβοτΜφΜίοτορΒΙ, areHTbi noBbiiueHnn κπβΜκοοτΜ, CTa6nnn3aTopbi, BemecTBa-Hocmenii, no6aBKM, perynnpytomne ΑΜφφν3Μ0ΗΗΗβ m neHeTpaqMOHHbie npoueccbi, μπμ BemecTBa - HanonHMTenM. PaccMaipMBaeMbie nrm stmx qenePi, He Bbi3biBaiomMe φΜ3ΜΟΠΟΓΜΗβΟ<ΜΧ ΟΠΘΟβΗΜΜ BeiiļeCTBa M3BeCTHbl CneLļManMCTaM.
Pe3epByapHbiPi chom oSnaflaeT τθκομ cnoco6HOCTbto κ noBbiujeHMio κπθμκοοτμ, KOTopaa oSecneHMBaeT ηθαθχηο AnMTenbHbiM Komraicr k κοχβ. npHMepaMM npnrOflHblX ΠΠ30ΤΜφΜΚ3ΤθρθΒ MOryT Cny)KMTb ΑΜ3φΜρΝ flMKap60H0BblX KMcnoT, HanpMMep, AM-H-6yTMn-aAMnaT, aTaoce mnqepMflbi, rne b nepByto onepeAb mojkho Ha3BaTb TpnrnnqepMAbi co cpeAHeii απμηομ qenn KanpMnoBOM/KanpnHOBOM KMcnoTbi κοκοοοβογο Macna.
MexcAy ΜβτριίΜθίί /1/ m noKpbiBHbiM cnoeM /4/ pacnonaraeTcn xpaHMnnme 6μοπογμηθοκμ aicmBHoro BemecTBa 32/. Oho coctomt M3 TeKCTMAbHoro o6pa30BaHMH m pacTBopa φΜ300ΤΜΓΜΜΗ3. TeKCTMflbHOe 06pa30B8HMe ΜΟΧΘΤ 6blTb B BMAe Kpyrnoii 3arOTOBKM M3 HeTKaHoro MaTepiiana /cMecb βοποκοη, βμοκο3ηοθ βοποκηο/ b οοοτηοιηθημμ 50:50, y κοτοροΓΟ Bec eAMHmļbi noBepxHOCTM (Χχπήβπβθτ 40 γ/μ2 μπμ xe 80 γ/μ2/ c ΑΜ3ΜβτροΜ οτ 20 αο 50 μμ. Βο3μοχηο Taioice πρμμθηθημθ μ Apymx TeKCTnnbHbix MaTepnanoe η, οοοτβθοτβθηηο, Apyrnx pa3MepoB AHaMeTpa. B κθηθοτβθ οοθαμηθημβ c, no KpaMHeii Mepe, oahom κμοπομ rpynnoft npeAnoHTmenbHbiM Bbicume xnpHbie KMcnoTbi, TaK xax pa3Mep βο3μοχηογο pa3ApaxeHMH, Bbi3BaHHbiM ΜΜφΜρΟΒΒΗΜβΜ ΚΜΟΠΟΤ, 33BMCMT OT AHMHbl ί1βΠΜ KMCflOTbl. llpMMepaMM ΠρΜΓΟΑΗΗΧ ΚΜΟΠΟΤ cnyxaT MacnnHan KHcnoTa, M30CTeapHH0Ban KncnoTa, yHAoqnnoBaa KMcnoTa m BepcaTMKOBan KMcnoTa. OTAenneMbiM 3aiAMTHbiii cnon, kotopum HaxoAMTcn b οοπρμκοοηοβθημμ c pe3epeyapHbiM cnoeM, m 6yAeT yAaneH nepeA πρμμθηθημθμ, coctomt, HanpMMep, M3 Tex xe caMbix MaTepManoB, KOTOpbie Mcnonb3yiOTCA απα μ3γοτοβπθημβ ποκροβηογο cnon /4/, npM ycnoBMM, ητο oh αοπχθη 6biTb oTAenneMbiM, HanpMMep, nocpeACTBOM ομπμκοηοβομ o6pa6oT«M. flpyrMMM OTAenneMblMM 3aiHMTHblMM CnOBMM MOryr 6blTb, HanpMMep, ΠΟΠΜΤβΤρβφΤΟρβΤΜΠβΗ, o6pa6oTaHHaa 6yMara, uennocpaH, ποπμβμημπχπορμα m APyrMe.
Ecjim npeAnaraeMbiM b οοοτβθτοτβμμ c α&ηημμ ΜβοδρβτβΗΜβΜ naMMHaT nepeA HaHeceHMeM 3amMTHOro cnon 6yAeT pa3AeneH Ha npMMeHneMbie b TepanMM φορΜθ^ι /KycoHKM nnacTbipa/, to noAnexaiuMe HaHeceHMio φopMaτbl 3amMTHoro cnon, b stom cnyHae, 6yAyT MMeTb BbicTynaiomMe KOHiļbi απβ τογο, htoGu c mx noMOiubio ohm μογπμ 6biTb nerxo OTAeneHbi οτ nnacTbipn. Ημχθ 6onee ποαρο6ηο ποβοηηιοτ onepauMM no Μ3γοτοβπθημιο. 5 LV 10383 Πρβχρθ βοθγο npuroTaBnuBaeTCfl MaTpmja IV, cocTaB κοτοροπ yKa3biBaeTCH b OTpenbHbix peqenTypHbix npnMepax. riocne yflaneHiia noKpbieaioineM ππθηκμ 6ypeT cpenaHa Kpyrnan 3aroTOBKa m ηθτκθηογο Maiepnana, noBepxHOCTb κοτοροπ αοπχηθ cociaBnnTb 13,72 cm2. b KanecTBe ηθτκθηογο Maiepnana πρμμθηπθτοπ Maiepnan M3 ομθομ βοποκοη BMCK03bl/xn0nKa B COOTHOLUeHMM 70:30 C BeCOM eflMHMlļbl ΠΟΒβρΧΗΟΟΤΜ 40 Γ Ha KBaflpaTHblPi Μθτρ. 3aieM m MaipuMbi c ηθποχθηηομ Ha Hee 3aroTOBKoPi Bbipe3aiOT npnMoyronbHMK nnomaflbK) 56 cm2. Kpyrnan 3aroTOBKa m Maipnpa M3o6paxeHbi Ha φΜ^ρθχ 1 m 2.
Tenepb c noMouļbio cooTBeTCTByioinero npncnoco6neHkm, HanpHMep, c noMOiiibK) KanenbHoPi πμπθτκμ Φμτοοτμγμμη - 25%-HbiM b MacnflHOM κμοποτθ m 35%-HbiPi b yHfleLļnnoBOii κμοποτθ - HaHOCMTCH Ha HeTKaHbiii MaTepnan. ToHHbie κοπμηθοτβθ ycTaHaBmiBaioTCfl b OTflenbHbix peuenTypax. riocne HaHeceHkm xpaHnnnme 6μοπογμηθοκμ βκτμβηογο BemecTBa/2/ m MaipMLļa /1/ 6ynyT HaKpbITbl ΠΟΚρΟΒΗΟΜ ΠΠΘΗΚΟΡί /4/. ΠθΚρθΒΗΝ& CflOM 3T0 ΚΠΘΘΒΟΜ cnoii, KOTOpbIM COCTOMT M3 MynbTnaKpnn-cononMMepa, HaHOCMMoro Ha πoπM^φMpHyιo nneHKy τοπιαμηομ 15 mkm. Ποοπθ ynarieHMfl pacBopMTenn Bec θαμημαν ποβθρχηοοτμ coCTaBnneT 30 γ/μ2. Ποοπθ noKpbiTMa 6ypeT BbiceneHa Kpyman noBepxHOCTb pa3MepoM 21,23 cm2, TaK hto nporiMTaHHaa 6μοπογμηθοκμ aKTHBHbiM BeaļecTBOM 3aroTOBKa H3 HeTKaHoro MaTepHana 6yneT ηθχοαμτ«;π b cepeAMHe /cMOTpme φΜΓγρΒΙ 3 h 4/. B 33κπιοηθημθ Kpaa 6ynyT oāpeiueTHeHbi m nonyHeHHaa TpaHCflepManbHan τθρθπθβτμηθοκθη ομοτθμθ BbiAepxMBaeeTcn βτθηθημθ 14 αηθμ πρπ 40°C. 06pa30BaHne npeAnaraeMoPi no Μ3ο6ρθτθημκ) ομοτθμν πρθαοτθβπθηο Ha φπ^ρβχ 1-4.
Ha φΜ^ρβ 1 npeflCTaBneH BMA Ha 3ar0T0BKy M3 ηθτκβηογο Maiepnana/2/, KOTopaa HaKnaAbiBaeTcn Ha Maipnuy /1/. Ποοπθ ηθποχθημπ 33γοτοβκη /2/ M3 ηθτκθηογο Maiepnana Ha MaTpMpy /1/ 6yAeT HaHOCMTbca χμακθπ κομπο3Μαμπ 6μοπογμηθοκμ 3κτμβηογο BemecTBa, Gnaropapa neMy 6yAeT o6pa30BaHO xpaHMnMme 6μοπογμηθοκμ θκτμβηογο BemecTBa /2/. B 33ΚΠΙ0ΗΘΗΜΘ C HOMOlAbK) Κ31ΠΜρθΒ3ΗΜΠ HBA MaTpMLļePi /1/ Μ ΧρβΗΜΠΗΙΑΘΜ δΜΟΠΟΓΜΗΘΟΚΜ aKTHBHoro BemecTBa /2/ HaHOCMTcn noKpoBHbiPi cnoii /4/. Ποοπθ ηθγο ocymecTBnfleTCfl lUTaHueBaHMe. Kpan 6ypyT οταθηθημ c noMOUļbio peiueTHaTOM Bbipy6KM.
Ha φΗΓγροχ 2 h 3 noKa3anb! οχθμ3τμηθοκμ bha ceepxy AJ)Mrypa 2/ h ποπθρθμηοθ ΟΘΗΘΗΜΘ /φΜΓγρθ 3/ Η3ΑΘΠΜΠ, ΓΑΘ ΗΘΓΠΠΑΗΟ BMAHO ρβΟΠΟΠΟΧΘΗΜΘ XpaHMnMUļa 6μΟΠΟΓΗΗΘΟΚΗ βκτμβηογο BemecTBa /2/ Ha Maipnue /1/ h pacnonoxeHMe κοηθμηογο πβρθκρΜΤΜπ /3/ nocne ujTaHLļeBaHHn. 06ihmm bha CMCTeMbi - eē nonepenHoe οθηθημθ M3o6paxeH Ha φπ^ρβ 4. 06o3HaHeHMfl B ΑΜφρβΧ Ha φΜί7Ρ8Χ 1 -4 03Η3Η3Κ)Τ: 1 - Maipnua 2 - ΧρβΗΜΠΜΙΑΘ ČMOnorMHeCKM ΘΚΓΜΒΗΟΓΟ ΒΘΙΑΘΟΤΒΘ ΜΠΜ ΧΘ Kpyf7iafl 3arOTOBKa M3 ηθτκθηογο MaTepnana 3- 3aUļHTHblM /ΚΟΗΘΗΗΟΘ ΠβρβΚρΒΙΤΜθ/ ϋΠΟΜ
4 - nOKpOBHblii CnOM 5 - MeTannMHecKan nneHKa ^onbra/ 6 npuMepbi peuervrypi npMMep 1 Μ3Γοτοβπθημθ MaipuLibi: 10,91 κγ40%-ογο pacTBopa caMOCiAMBaiomeroca aKpunaT-cononuMepa 2-3TMn-reKcnn-aKpnnaTa, BMHMnaLieTaTa μ θκρμποβομ KMcnoTbi c τμτθη-χθπθτ-cno>KHbiM 3φΜροΜ, CMecb pacTBopMTeneii /βτιιπθΐ^θτβτ: βτθΗοπ : renTaH : μθτθηοπ = 64 :25:9: 2 / μ 2,4 κγ 50%-oro pacTBopa κβτμοηηογο cononnMepn3aTa Ha οοηοβθ αμμθτμπ3μμηο3τμπ-MeTaKpunaTa μ HempanbHoro strupa μθτθκριιποβομ κμοποτν β sTunapeTaTe 6binn CMeuiaHbi c 360 r TpurnMMepnflOB KanpunoBoii/KanpMHOBoii KucnoT npn KOMHaTHoii TeMnepaType, v\ npn nepeMemMBaHMM. C noMombra οοοτβθτοτβυιοιιιθγο patcenn ηθηοοατ nonyMeHHbiii cocTaB Ha nonk^npHyio nnēHKy c HanbīneHHbiM θπιομμημθμ m HaKpbieaiOT ποπμμθρηομ ππθηκομ /m3 nonn3TnneHa - hh3kom πποτηοοτμ/.
Bec eflMHMUbi noBepxHOCTM αοπχθη cocrraBrmTb ot 260,00 no 275 γ/μ2.
CocTaB MaipMLļbi 1: caMOCLUHBaioinMHCH aKpMnaT cononMMep ACP-ļ 74%
MeTaKpnnaT-cononnMep MCP 20%
TpMpmMLļepMAbl KanpMnOBOM/KanpMHOBOM KMCnOTTriC- 6% 100% Ποπμ3τμπθηοβ3η nnēHKa 6yneT ynaneHa μ ηβποχθη ηθίίώημΚ MaTepiian β βμαθ 3aroTOBKM. Ha ηθτιοημμ Maiepnan c noMOUļbio KanenbHoPi πμπθτκμ 6yneT HaHOdiTbca CMecb 12 ΜΓ φΜ300ΤΜΓΜ11Η3 M 36 ΜΓ MaCflflHOM KMCnOTbl.
Bce nocneflyiou4Me npMMepbi m npmviep 1 npMBejļeHbi b cnenyioii|MX Ta6nniJiax, npeflCTaBneHHbix b npnnopxeHHn. BbifleneHiie ”in vitro” 6bino onpepeneHO b boaahom čaHe co BCTpaxnBaHneM npM 37°C. Β κθηθοτβθ θκαθπτορηομ cpeflbi cnyxnnn 100 μπ Φμ3μοπογμηθοκογο pacTBopa noBapeHHoPi conu, KOTopbiii nonHOCTbio CMeHnncn nocne 2, 4 v\ 8 nacoB, KoHueHTpaumi nocne 2, 4, 8 h 24-x nacoB onpeflennnMCb πρκ noMomn Υφ - cneicrpocKonMH. npMBepeHHbie b Ta6nnuax 3Ha4eHnn βμαθπθημη flBnmoTcn cooTBeTCTByiomMMM cyMMaMM M3MepeHHblX KOHLļeHTpaUMki.
Ta6nnua 1 noKa3biBaeT o6pa30BaHne h ”in vitro” BbipeneHMe b npnMepax I- IY. B sthx npMMepax ncnonb30Banacb opHa m Ta xe MaTpiiua, ho κοπμηθοτβο HaneceHHoro BemecTBa BapbMpoBanocb; 6bin HaHeceH Φμ30οτμγμμη β βμαθ 25%-oro pacTBopa b MacnnHoPi κμοποτθ. npM 3T0M yCTaHOBMnM, HTO C pOCTOM COflepxaHMfl /flOHH/ φΜ300ΤΜΓΜΜΗ3 B03paCTaeT ΗΘ TonbKO a6coniOTHoe, ho τθιοκθ h OTHOcmenbHoe BbifleneHMe.
Ta6nnua 1
BbifleneHMe /μγ/ /%/ flpHMep ΦΜ300ΤΜΓΜΜΗ rc 2 Η 4 Η 8 Η 24 η 24 Η 1 12 μγ 260 1,64 2,28 3,17 5,62 46,8 II 12 μγ 180 3,28 4,60 6,29 9,19 76,6 III 16 μγ 260 2,77 4,03 6,71 10,38 56,1 IY 20 μγ 180 6,43 9,15 12,76 17,47 87,4 fC = Bec eflMHMUbi noBepxHOCTM MaTpmļbi - γ/μ2. 7 LV 10383 B npnMepax IY - XXIII A03npoBanncb 20 μγ Φμ30οτμγμμη3, pacTBopeHHbie b 60 μγ MacnaHOM KMcnoTbi. BapbnpoBanncb npoueHTHbi\h cociaB MaTpuMbi m eec emmiļbi ποβθρχηοοτμ /ΓΌ/. flaHHbie MaTpmļbi npencTaBneHbi b TaSnuue 2. B Ta6nnqax Mcnonb30BaHrbi cneflyiOLMMe coKpameHMa: ACP-j - caMOCLUMBaKDiiļuPicj) aKpunaT-cononuMep ž-sjvmreKcmaKpmacra, BMHunaueTaia m aKpMHOBOM kmchotn c THTaH-xenaT-30npoM b KanecTBe cpepcTBa clumbkm; ACP2 - HecaMocujMBaKDiuMMCB aKpunaT-cononuMep 2-3TnnreKCMnaKpnnaTa, BMHMnaqeTaTa m aKpMHOBOM KMcnoTbi; NCP * C0n0nMMepM3aT Ha OCHOBe ΑΜΜΘΤΜΠΒΜΜΗ03ΤΜΠΜΘΤ3ΚρΜΠ3Τ3 M HefrrparibHOrO cno>KHoro 3φΜρβ ΜΘΤ3ΚρΜΠ0Β0Μ KMCHOTbl;
TriG - TpMrnuuepMAbi KanpMHOBOM/KanpMHOBoti kmchot; K.E. - CHOJKHblM 3φΜρ CMOHHHOM KMCHOTbl ΚβΗΜφΟΠΜ C mMLļepilHOM. B npnMepax ΧΧΙΥ - XXXI fl03MpoBanMCb 20 μγ Φμ30οτμγμμη3, cMeiuaHHbie c 37 μγ yHfleunnoBoii KucnoTbi. BapbupoBanncb npoueHTHbiM cocTaB MaTpuiļ μ βθο ποβθρχηοοτμ; AaHHbie MaTpMiļbi npMBefleHbi b Ta6nMqe 3. OMrypbi 5 m 6 noKaebiBaioT xapaicrep ”in vitro” - βναθπθημη b npMMepe XXX. Tax KaK BbifleneHHbie κοπμηθοτβ3, npeflCTaBneHHbie b βμαθ 38βμομμοοτμ ot κορηη /κβθαρθτηογο/ M3 ΒρΘΜΘΗΜ, - KaK ΠΟΗΤΜ BO ΒΟΘΧ HpMM6paX - flaiOT npflMyiO, ΜΟ)ΚΘΤ 6blTb noKa3aHO, HTO 6bina pa3pa6oiaHa ομοτθμθ, KOTopaa nocpeflCTBOM ynpaBneHMH MaTpMLjetf, KOHTponMpoBaHHO "OTflaēT” Ομοπογμηθοκμ aKTMBHoe βθιμθοτβο, Tax ητο οαηο3Η3ηηο βηποπηηκπόη TpeāOBaHMfl ΜΟΑΘΠΜ XMryMM.
Bmaho, mto BbifleneHMe μοπηρηογο οτηοιιιθημη Kap6oHOBbix kmchot k 6a3MCHOMy nonMMepy 6bino οπρθαθπθηο. Μοχηο OTMeTMTb, ητο βηαθπθημθ τθμ Bbime, ηθμ MeHbuue 6bino ΒΒΘΑΘΗΟ KMCHOTbl Μ ΗΘΜ ČOHbLUe 6a3MCH0T0 ΠΟΠΜΜΘρβ. ΒΝΑΘΠΘΗΜΘ ΤΘΜ BbllUe, ΗΘΜ MeHbUie HeflMCCOLļMMpOBaHHOM KMCHOTbl npMCyTCTByeT B ΟΜΟΤΘΜΘ ΠΟΟΠΘ Bblflep>KKM; TaK KaK B MOHflpHblX κοπμηθοτβθχ yHfleqMnoBOM kmchotn Mcnonb30Banocb MeHbuie, ηθμ μθοπηηομ κμοποτμ, ποηητηο, noneMy πρΜ οαηομ μ τοΛ χθ μητρμαθ o6pa3eq c yHfleqMnoBOM kmchotom βμαθπηθτ /”οοβο6ο>καβθτ7 Φμβοοτμγμμηθ 6onbuie, ηθμ o6pa3eq c MacnHHOM κμοποτομ. nocpeflCTBOM φρ3Κ11Μ0ΗΜρ0Β3ΗΜΗ ΠΠΘΟΤΜφΜΚΘΤΟρΘ ΜΟΧΘΤ 6blTb npOfleMOHCTpMpOBaHO, ΗΤΟ ΠΠβΟΤΜφΜΚβΤΟρ ΗΘ ΜΜΘΘΤ ΗΜΚΘΚΟΓΟ ΒΠΜΗΗΜΗ Ha nOLļeCC Ίπ Vitro” - ΒΗΑΘΠΘΗΜΗ.

Claims (16)

  1. LV 10383 IZGUDROJUMA FORMULA 1. Transdermālā terapeitiskā sistēma, kas satur aktīvo vielu necaurlaidīgu pārklāja slāni, lipīgu rezervuāra slāni un, nepieciešamības gadījumā, atdalošos aizsargslāni, fizostigmīna ievadīšanai ādā, kas a t š ķ i r a s ar to, ka rezervuāra slānis satur 10-90 sv.% polimēra materiāla, ko izvēlas no grupām, tādām kā blokkopolimēri uz stirola vai 1,3-diēna bāzes, poliizobutilēni, polimēri uz akrilāta, un/vai metakrilāta bāzes vai hidrēti kolofonija esteri; līdz 30 sv.% pIastifikātora un ogļūdeņražu bāzes un/vai esteri; un ka aktīvās vielas depo tieši pēc pagatavošanas satur no 15 līdz 85 sv.% fizostigmīna šķīduma ar koncentrāciju no 0,1 līdz 70 sv.%.
  2. 2. Transdermālā terapeitiskā sistēma, saskaņā ar 1. punktu, kas a t š ķ i r a s ar to, ka polimēra materiāls ir 2-etiIheksiIakriIāta, vinilacetāta, akrilskābes un titāna helāta estera pašsaistīties spējīgais akrilāta kopolimērs.
  3. 3. Transdermālā terapeitiskā sistēma, saskaņā ar 1. punktu, kas a t š ķ i r a s ar to, ka polimēra materiāls ir 2-etiIheksiIakriIāta, vinilacetāta un akrilskābes pašsaistīties nespējīgais akrilāta kopolimērs.
  4. 4. Transdermālā terapeitiskā sistēma, saskaņā ar 1. punktu, kas a t š ķ i r a s ar to, ka polimēra materiāls kā polimēru uz metakrilātu bāzes satur kopolimēru uz dimetilaminoetilmetakrilāta un metakrilskābes neitrālo esteru bāzes.
  5. 5. Transdermālā terapeitiskā sistēma, saskaņā ar 1. punktu, kas a t š ķ i r a s ar to, ka polimēra materiāls kā hidrētu kolofonija esteri satur tā metilesteri.
  6. 6. Transdermālā terapeitiskā sistēma, saskaņā ar 1. punktu, kas a t š ķ i r a s ar to, ka polimēra materiāls kā hidrētu kolofonija esteri satur tā glicerīna esteri.
  7. 7. Transdermālā terapeitiskā sistēma, saskaņā ar 1. punktu, kas a t š ķ i r a s ar to, ka rezervuārais slānis kā plastifikātoru satur dioktilcikloheksānu.
  8. 8. Transdermālā terapeitiskā sistēma, saskaņā ar 1. punktu, kas a t š ķ i r a s ar to, ka rezervuārais slānis kā plastifikātoru satur di-n-butiladipātu.
  9. 9. Transdermālā terapeitiskā sistēma, saskaņā ar 1. punktu, kas a t š ķ i r a s ar to, ka rezervuārais slānis kā plastifikātoru satur triglicerīdus.
  10. 10. Transdermālā terapeitiskā sistēma, saskaņā ar 1. punktu, kas a t š ķ i r a s ar to, ka rezervuārais slānis kā plastifikātoru satur izopropilmiristātu.
  11. 11. Transdermālā terapeitiskā sistēma, saskaņā ar 1. punktu, kas a t š ķ i r a s ar to, ka fizostigmīna šķīduma šķīdinātājs aktīvās vielas depo ir savienojams ar vismaz vienu skābes grupu.
  12. 12. Transdermālā terapeitiskā sistēma, saskaņā ar 11. punktu, kas a t š ķ i r a s ar to, ka savienojums ar vismaz vienu skābes grupu ir karbonskābe.
  13. 13. Transdermālā terapeitiskā sistjma, saskaoā ar 12. punktu, kas a t ņ i i r a s ar to, ka karbonskābes ietilpst sviestskābe un undecilskābe. 2
  14. 14. Transdermālā terapeitiskā sistēma, saskaņā ar 12. punktu, kas atšķiras ar to, ka karbonskābēs ietilpst oktadekānskābju maisījums.
  15. 15. Transdermālā terapeitiskā sistēma, saskaņā ar 12. punktu, kas a t š ķ i r a s ar to, ka karbonskābēs ietilpst versatikskābes.
  16. 16. Transdermālās terapeitiskās sistēmas iegūšanas paņēmiens, saskaņā ar 1. punktu, kas a t š ķ i r a s ar to, ka fizostigmīnu vai tā farmaceitiski pieņemamu sāli šķīdumā uznes uz tekstilmateriāla, kas atrodas uz iepriekš sagatavotas pašpielīpošas, nepieciešamības gadījumā, apgādātas ar noņemamu aizsargslāni, matricas, pie tam matrica un aktīvās vielas depo ir apgādāti ar pārklāja slāni.
LVP-93-1012A 1988-12-22 1993-08-06 Transdermal therapeutic system and method for producing thereof LV10383B (en)

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