HRP20040751A2 - Aerosol formulations for pulmonary administration of medicaments to produce a systemic effect - Google Patents
Aerosol formulations for pulmonary administration of medicaments to produce a systemic effectInfo
- Publication number
- HRP20040751A2 HRP20040751A2 HRP20040751A HRP20040751A2 HR P20040751 A2 HRP20040751 A2 HR P20040751A2 HR P20040751 A HRP20040751 A HR P20040751A HR P20040751 A2 HRP20040751 A2 HR P20040751A2
- Authority
- HR
- Croatia
- Prior art keywords
- pharmaceutical formulation
- formulation according
- hfa
- aerosol
- ethanol
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims description 65
- 238000009472 formulation Methods 0.000 title claims description 55
- 239000003814 drug Substances 0.000 title claims description 44
- 239000000443 aerosol Substances 0.000 title claims description 33
- 230000009885 systemic effect Effects 0.000 title description 7
- 230000002685 pulmonary effect Effects 0.000 title description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 108
- 229940079593 drug Drugs 0.000 claims description 41
- 239000002245 particle Substances 0.000 claims description 26
- -1 polyoxyethylene Polymers 0.000 claims description 25
- 239000003380 propellant Substances 0.000 claims description 25
- 239000006184 cosolvent Substances 0.000 claims description 23
- 150000005828 hydrofluoroalkanes Chemical class 0.000 claims description 19
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- 239000010419 fine particle Substances 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- YFMFNYKEUDLDTL-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical compound FC(F)(F)C(F)C(F)(F)F YFMFNYKEUDLDTL-UHFFFAOYSA-N 0.000 claims description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 229920005862 polyol Polymers 0.000 claims description 6
- 150000003077 polyols Chemical class 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 229920001515 polyalkylene glycol Polymers 0.000 claims description 5
- 150000001298 alcohols Chemical class 0.000 claims description 4
- 125000005907 alkyl ester group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims description 3
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 3
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 claims description 3
- 150000002170 ethers Chemical class 0.000 claims description 3
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims description 3
- 229940093471 ethyl oleate Drugs 0.000 claims description 3
- 229930195729 fatty acid Natural products 0.000 claims description 3
- 239000000194 fatty acid Substances 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 claims description 2
- 239000008249 pharmaceutical aerosol Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims 1
- 235000019441 ethanol Nutrition 0.000 description 39
- 108010000817 Leuprolide Proteins 0.000 description 13
- 229960004338 leuprorelin Drugs 0.000 description 13
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 12
- 238000012384 transportation and delivery Methods 0.000 description 10
- 238000012360 testing method Methods 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 8
- 238000000151 deposition Methods 0.000 description 8
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- 210000004072 lung Anatomy 0.000 description 8
- 229910052751 metal Inorganic materials 0.000 description 8
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- VNUZLUGZUNVCTB-LJQANCHMSA-N [(6ar)-6-methyl-11-(2-methylpropanoyloxy)-5,6,6a,7-tetrahydro-4h-dibenzo[de,g]quinoline-10-yl] 2-methylpropanoate Chemical compound CN1CCC2=CC=CC3=C2[C@H]1CC1=CC=C(OC(=O)C(C)C)C(OC(=O)C(C)C)=C13 VNUZLUGZUNVCTB-LJQANCHMSA-N 0.000 description 6
- 229910052782 aluminium Inorganic materials 0.000 description 5
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
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- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000000977 initiatory effect Effects 0.000 description 3
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- 239000007858 starting material Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
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- 229940035676 analgesics Drugs 0.000 description 2
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- 239000003242 anti bacterial agent Substances 0.000 description 2
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- 229940088710 antibiotic agent Drugs 0.000 description 2
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- 230000015556 catabolic process Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
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- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
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- SFVVQRJOGUKCEG-OPQSFPLASA-N β-MSH Chemical compound C1C[C@@H](O)[C@H]2C(COC(=O)[C@@](O)([C@@H](C)O)C(C)C)=CCN21 SFVVQRJOGUKCEG-OPQSFPLASA-N 0.000 description 1
Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
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- 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
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4704—2-Quinolinones, e.g. carbostyril
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
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- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- 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
Description
Područje izuma
Ovaj izum odnosi se na aerosolne otopine u formulacijama koje sadrže lijek, propelant, jedan ili više kootapala i mogu biti prisutni drugi aditivi koji se često koriste u ovim vrstama formulacija.
Dosadašnje spoznaje
S mnogim farmaceutski aktivnim spojevima koji se sada koriste u kliničkoj praksi ima problema pri davanju i/ili apsorpciji oralno, parenteralno ili transdermalno te može biti pogodno dati ih pulmonarnom isporukom, a da se dobije sistemski učinak.
Farmaceutski aktivne tvari mogu biti dane u respiratorni trakt upotrebom inhalatora s odmjerenom dozom pod tlakom (pMDI). pMDI koriste propelant da izbaci kapljice u respiratorni trakt koje sadrže farmaceutski produkt u obliku aerosola.
Formulacija može biti otopina ili suspenzija. Kod formulacija otopina, za razliku od suspenzija nema problema vezanih za fizikalnu stabilnost suspendiranih čestica i tako se može garantirati dobivanje jednolične veće doze i reproducibilost.
Što se tiče tipa propelatna, hidrofluoralkani (HFA - poznati kao hidrofluorugljici HFC) će biti obavezni propelatni jer su klorfluorugljici (poznati kao freoni ili CFC), a koji su godinama bili preferirani propelanti u aerosolima za farmaceutsku upotrebu, zabranjeni zbog djelovanja na okoliš.
1,1,1,2-Tetrafluoretan (HFA 134a) i 1,1,1,2,3,3,3,-heptafluorpropan (HFA 227) su najbolji kandidati za ne-CFC propelante i prikazane su brojne farmaceutske formulacije koje koriste HFA sustav propelanta.
Prikaz izuma
Namjera je prikazati formulacije otopine u HFA propelanta za aerosolnu isporuku lijekova da se dobije brzi sistemski aktivna doza rečenog lijeka via prespiratornog trakta.
Od sada se termin lijek koristi da definira bilo koji farmaceutski aktivni spoj koji može biti pogodno isporučiti u pluća i tako dobiti sistemi terapijski učinak.
Da bi se dobila terapijski korisna razina u plazmi, treba dostići terapijsku koncentracija lijeka i učinkovitu isporuku aerosola.
Važni parametar za učinkovitu isporuku aerosola da se dobije sistemski terapijski učinak je raspodjela veličine čestica u aerosolnom oblaku. Kada je formulacija u obliku suspenzije, veličina čestica u oblaku je određena veličinom čestica suspendiranog lijeka, definirano postupkom mljevenja/usitnjavanja.
Kada je formulacija u obliku otopine, nema volumetrijskog doprinosa suspendiranih čestica lijeka i generiraju se mnogo finije kapljice u oblaku, uglavnom definirane koncentracijom lijeka u otopini.
Veličina čestica prikazana kao pMDI je normalno izražena kao aerodinamički dijametar medijalne mase (MMAD). Veličina čestica od izbora aerosolnih lijekova za tretman bronhopulmoranih bolesti je obično približno 3 μm. Preferirani promjer aerosolnih čestica ili kapljica je između 0.5 i 5 μm.
Kada je lijek isporučen u pluća pomoću inhalatora s odmjerenom dozom, a da se dobije sistemski učinak, čestice trebaju biti dovoljno male da se isporuče u pluća i da budu apsorbirane u krvotok nakon inhalacije, tj. pogodno je da je veličina između oko 0.5 μm i 2.5 μm (MMAD od oko 1-2 μm). Čestice manje od 0.5 μm nisu terapijski korisne jer budu izdahnute.
Formulacije aerosolnih otopina nude pogodnost homogenosti aktivne tvari i ekscipijensa koji su potpuno otopljeni u propelantnom vezikulu ili u njihovoj smjesi s pogodni kootapalom kao što je etanol. Formulacija otopine također otklanja probleme fizičke stabilnosti povezane sa formulacijama suspenzije, stoga osigurava reproducibilnost doziranja.
Štoviše, kada je potreban sistemski učinak, kao što je slučaj izuma, aerosolna formulacija nudi prednost jer su generirani mnogo finiji oblaci, uglavnom definirani koncentracijom lijeka u otopini, a finiji oblaci uzrokuju bolju depoziciju u perifernom dijelu pluća.
Kada je lijek slabo topljiv u HFA propelantima kao što je HFA 134a i HFA 227 ili u njihovoj smjesi, potrebna je upotreba otapala, općenito etanola.
Kada je lijek vrlo slabo topljiv u HFA propelantu potrebna je velika količina etanola. S druge strane, velika količina etanola smanjuje koncentraciju lijeka i veličinu aeroslnih kapljica koje napuštaju otvor pokretača. Veće kapljice se više deponiraju u orofaringalni trakt čime se gubi udio lijeka koji prodire u niže dišne puteve (udio koji se udiše). Mala je vjerojatnost da mali udio koji se udiše poveća razinu lijeka u serumu toliko koliko je potrebno da se dobije terapijski učinak.
Štoviše, povećana količina etanola u formulaciji znači povećanu količinu zaostale vode. Dok je količina vode do 10% w/w, preferirano od 0.5 i 8% w/w, preferiranije između 0.5 i 6% u mnogim slučajevima korisna za poboljšanje topljivosti lijeka u sustavu preopelant/kootapalo, u drugim slučajevima prisutnost vode može povećati degradaciju lijeka i može smanjiti fizičku stabilnost formulacije i povećati nehomogenost sustava.
Bilo bi pogodno prikazati formulaciju za pulmonarnu isporuku koja bi se koristila u inhalatorima s odmjerenom dozom pod tlakom, a koja je kemijski i fizički stabilna i može nakon pokretanja dati pogodnu dozu finih čestica (FPD) i dobar udio koji se udiše (FPF) uzrokujući ranu terapijsku razinu lijeka u plazmi. Doza finih čestica ili doza koja se udiše je količina aktivnih čestica veličine manje od 4.7 μm a udio finih čestica ili udio koji se udiše je omjer između udahnute doze i doze isporučene nakon pokretanja inhalatora. Udahnuti udio bi trebao biti najmanje 30%, preferirano više od 40%, čak preferiranije više od 50% isporučene doze.
Bit će vrlo pogodno dobiti formulaciju čija je isporučena doza visoko resproducibilna nakon ponovljenih davanja iz pMDI.
Kako bi visoko sistemsko izlaganje aerosolnim česticama trebalo u ovom slučaju biti pogodno, bilo bi čak pogodnije da se dobije formulacija u kojoj je cijeli sustav otapala podešan da dozvoljava generiranje aeroslnih čestica koje mogu duboko prodirati u pluća, a u isto vrijeme svesti na najmanju mjeru količinu vrlo malih čestica (≤0.5 μm) koje bi bile izdahnute.
Izum prikazuje rješenje rečenih problema pomoću otopine formulacija koje sadrže lijek, HFA propelant a može i kootapalo. Rečene otopine su kemijski stabilne u adekvatnom vremenskom intervalu i mogu nakon pokretanja davati udio koji se udiše kojim brzo nastupa terapijska razina lijeka u plazmi.
Preferirana kootapala su niži alkil (C1-C4) alkoholi, polioli, polialkilenglikoli i njihove kombinacije.
Etanol je posebno preferiran.
Ostala pogodna kootapala su (poli)alkoksi derivati uključujući polialkoksi-alkohole, posebice 2-(2-etoksietoksi)etanol (na raspolaganju pod tržišnim nazivom Transcutol®).
Daljnji (poli)alkoksi derivati uključuju polioksialkil etere i estere kao što je polioksietilen eteri ili esteri. Prefeirani polioksietilen eteri ili esteri su polioksietilen-alkil-esteri, esteri masnih kiselina i polioksietilen-sorbitana te polioksietilen-stearati.
Kiselinski alkilni esteri se također mogu koristiti kao kootapalo. Preferirani kiselinski alkilni esteri su etil-oleat, izorpopil-miristat i izopropil-palmitat.
Prema preferiranoj cjelini izum prikazuje farmaceutski pripravak koji sadrži lijek, HFA propelant i količinu etanola do 30%, preferirano do 20%, preferiranije do 10% i kootapalo veće polarnosti od etanola u količini od 0.2% do 10% w/w, preferirano od 0.5 do 10% w/w, preferiranije od 0.5 do 6%, čak preferiranije od 1 do 2% w/w.
Polarnost se može kvantizirati i stoga usporediti prema dielektričnoj konstanti upotrebom Maxwellove jednadžbe kojom se uspoređuje dielektrična konstanta sfernog indeksa refrakcije - indeks refrakcije materijala se lako mjeri ili dobiva iz literature. Alternativno se polarnost kootapala može mjeriti upotrebom Kauribuanolne vrijednosti za procjenu snage otapala. Protokol je opisan u ASTM Standard: Designation 1133-86.
Dodatak kootapala s većom polarnosti od etanola dozvoljava smanjivanje količine etanola ostavljajući modulaciju veličine čestica kapljica dobivenog aerosola.
Preferirana kootapala veće polarnosti od etanola su preferirano odabrani od sljedećih: niži alkil (C1-C4) alkoholi, polioli, polialkilenglikoli.
Preferirani polioli uključuju propilenglikol i glicerol a preferirani polialkilenglikol je polietilenglikol.
Među kootapalima koji imaju veću polarnost od etanola treba razmotriti vodu. Količina vode, a kada je prisutna, je do 10% w/w, preferirano između 0.5 i 8% w/w, preferiranije između 0.5 i 6%.
Prema još preferiranijoj cjelini, izum prikazuje farmaceutski pripravak koji se sastoji od lijeka, HFA propelanta, može etanola u količini između 2 i 30%, preferirano između 5% i 20%w/w, preferiranije do 10%, a može i kootapalo. Pogodno je da je količina aktivnog sastojka najmanje 0.01% w/v a preferirano između 0.1 i 1.0% w/v.
Male količine etanola i kootapala su također korisne kada je lijek potpuno topljiv u propelantu.
Doista je nađeno da usprkos tome što otapalo nije potrebno za otapanje lijeka u propelantu, mala količina etanola (preferirano između 5-8% w/w, preferiranije oko 5% w/w) utječe na karakteristike depozicije čineći sistemsku isporuku lakšom jer etanol pomaže u smanjivanju količine vrlo malih čestica (<0.5 μm) koje mogu biti izdahnute zbog kratkog ostajanja u plućima. Štoviše, etanol smanjuje depoziciju materijala u otvoru inhalatora i time poboljšava reproduktibilnost nakon ponovljenih davanja održavanjem otvora pokretača 'čistim'.
Zbog tog efekta "čisćenja" etanol se općenito koristi kao površinski aktivna tvar, pa podmazivači ventila nisu potrebni.
U nekim slučajevima, međutim, formulacija može sadržavati male količine dodatnih komponenata kao što su površinski aktivne tvari ili drugi aditivi koji su konzervansi, puferi, antioksidanski, "hvatači" radikala, zaslađivači i sredstva za poboljšanje okusa.
Preferirane organske površinski aktivne tvari su odabrane od sljedećih: oleil-alkohol, sorbitan-trioleat, sorbitan-monooleat, polioskietilen (20) sorbitan-monolaurat, polioskietilen (4) eter, blok polimetil ili oksietilen ioksipropilen, oleinska kiselina, sintetski lecitin, dietilenglikol-dioleat, tetrahidrofurfuril-oleat, etil-oleat, izopropil-miristat, gliceril-monooleat, gliceril-monostearat, gliceril-miniricinoleat, etil-alkohol, sterailni alkohol, cetilni piridinijev klorid, maslinovo ulje, gliceril-monolaurat, kukuruzno ulje, ulje sjemenki pamuka ili suncokretovo ulje.
Prema daljnjem aspektu izum prikazuje metodu punjenja aerosolnog inhalatora s pripravkom iz izuma, a metoda sadrži:
(a) vaganje potrebne količine aktivnog sastojka u metalnu posudu ili bočicu,
(b) dodavanje odgovarajućeg volumena etanola i po potrebi dodatnog kootapala,
(c) stezanje ventila i gasiranje;
(d) dodavanje propelanta koji sadrži hidrofluoralkan (HFA).
Bilo koji lijek koji se može dati inhalacijom aerosola može biti solubiliziran u sustavu HFA/etanol/kootapalo te ako je apsorbiran u krvotok preko pluća može biti korišten u aerosolnpm pripravku iz ziuma. Primjeri rečenih lijekova su:
antagonisti ciclooksigenaze, mast stanica, lipoksigenaze i inhibitora proteolitičkih enzima, arakidonske kiseline, leukotriena, tromboksana, narijevih/kalijevih kanala, neurokinina, tahikinina, bradikinina, muskana, histamina, fosfodiesteraze i antagonisti selektina, blokatori kalijevih kanala, antiinfektivna sredstva, antibiotici, pentamidin, citostatici, fungistatici, uklanjači slobodnih radikala, vitamini, hormoni,
imunostimulanti, imunosupresanti, heparin, antidiabetici, analgetici, hipnotici i slično, primjerice:
- leukotriene antagonisti kao što je iralukast, zafirlukast i pranlukast,
- inhibitor lipoksigenaze kao što je zileuton,
- antagonisti natrijevih kanala kao što je amiloride, antagonisti kalijevih kanala, bimakalim,
- antagonisti arahidonske kiseline kao što je 2-benzoksazolamin,
- antagonisti histaminskog receptora kao što je epinastine, azelastine, cinarizine, cetrizine, mizolastine, mekvitamij, klorfeniramin, astemizole, terfenadin te fenoksfenadin,
- sredstva protiv migrene kao što su ergot alkaloidi metisergid, ergotamin, serotonin, sumatriptan, zolmitriptan, ciklandelate itd.,
- analgetici kao što je fentanil, morfin, buprenorfin, opium, heroin, nalbufin, pentazocin, oksikodon, tramadol, pethidin, tilidin, methadon, nefopam, dekstropropoksifene, piritramide, itd.,
- antiemetici kao što je bromprid, domperidon, metoclopramid, triethilperazin, trifIuoropromazin, meclozin, klorfenoksamin, dimenhidrinate itd.,
- antibiotici kao što su penicilini (npr. azlocilin), cefalosporini (npr. cefotiam ili ceftriaksone), karbapenemi, monobaktami, aminoglicozidei (npr. streptomicin, neomicIn, gentamicin, amikacin ili tobramicin), kinoloni (npr. ciprofIoksacin), macrolides (npr. erithromicin), nitroimidazoli (npr. tinidazol), linkosamid (npr. clindamicin), glicopeptidi (npr. vancomicin), polipeptidi (npr. bacitracin), mupirocin itd.,
- vitamini i uklanjači slobodnih radikala kao što su vitamin A, B, C, D ili E, catalaze, superoksid-dismutaze, reducirani glutation itd.,
- antidiabetici kao što je glibenclamid, glipizid, gliclazid, glimepiride, troglitazone itd.,
- hipnotici kao što su benzodiazepini, piperidonedioni, antihistaminici itd.,
- neuroleptici, antidepressanti i anticonvulsanti kao što su benzodiazepini, fenotiazini, butirofenoni, sulpirid, hidantoini, barbiturati, sukcinimidi, karbamazepine itd.,
- sistematski aktivni lijekovi kao što su primjerice izosilibid-dinitrate, izosilibide-mononitrate, apomilifin i kanabinoidi,
- antiinflamatorna sredstva,
- hormoni i njihovi sintetski analozi kao što su androgeni (npr. testosteron), antiestrogeni, LHRH, leuprolide-acetat, kalcitonin, parathirin, somatotropin, oksitocin, prolaktin, glukagon, eritropoietin, atriopeptin, melanotropin, tirotropin, gonadotropin, vazopresin, insulin, itd.,
- sredstva za potenciju kao što je alprostadil,
- citostatici kao što su derivatidušikovog mustarda (kao što je ifosfamid), derivati N-nitrozouree (npr. lomunstin), na purinu and pirimidinu zasnovani antagonisti (npr. fluiliouracil), kompleski platine (npr. karboplatin), antraciklini (npr. doksiliubicin), derivati podofilina (npr. podofilotoksin).
Mada su preferirani lijekovi iz izuma oni koji se obično ne daju kao pulmonarni aerosol, formulacije aerosolne otopine iz izuma se mogu pogodno primijeniti također na spojeve koji se već koriste u pripravcima za inhalaciju, primjerice beta-mimetici kao što je salmeterol, kortikosteroid preferirano odabran od triamcinolona, ciklezonid, flutikazon i mometazon; antikolinerigici kao što je oksitorpijev bromid i tiotropijev bromid; inhibitor mast stanica kao što je kromoligična kiselina, nedokromil itd.
Velika učinkovitost generiranja oblaka dozvoljava da se priprave formulacije koje sadrže lijek sa smanjenom normalnom dozom i većim postotkom klinički korisnom depozicijom lijeka, a u odnosu na referentni pripravak (FPF od najmanje 30%, preferirano više od 40%, preferiranije više od 50% isporučene doze), te s definiranom veličinom čestica koje ciljaju specifične dijelove pluća.
Rečeni lijekovi se mogu koristiti u obliku njihovih estera, izomera, enatiomera ili racemata, te u slučaju kiselina i baza kao takvih ili u obliku njihovih farmaceutski prihvatljivih soli.
Pogodno je da koncentracija aktivnog sastojak iznosi najmanje 0.01% w/v, preferirano najmanje 0.05% w/v, preferiranije između 0.1% w/v i 1.0 w/v, još preferiranije najmanje 1.0%^ w/v.
Preferirano je da je formulacija pogodna za isporuku terapijske količine aktivnog sastojka nakon jednog ili dvaju pokretanja. Prednost je da će formulacija biti pogodna za isporuku terapijske doze od najmanje 25 μg/dozi, preferirano između 50 i 500 μg/dozi. Pod "terapijska doza" je mišljeno da količina aktivnog sastojak isporučenog jednim pokretanjem inhalatora može producirati farmakodinamički učinak.
Formulacija iz izuma će biti punjena u spremnike pogodne za isporuku farmaceutske aerosolne formulacije. Neki lijekovi su podvrgnuti ubrzanom kemijskom raspadanju ako pri čuvanju dolaze u dodir s metalnim spremnikom koji su uobičajeno načinjeni od aluminija. U tim slučajevima će biti punjeni preferirano u posude koje imaju cijelu ili unutarnju površinu inertnu načinjenu od anodiziranog aluminija, čelika ili presvučenu organskim slojem. Primjeri preferiranog sredstva za presvlačenje površine su eposkifenolne smole, perfluoralkoksialkan, prefluoralkoksialkilen, perfluoralkileni kao što je poli-tetrafluoretilen, fluorirani etilen-propilen, polieterski sulfon i koolimer fluoriranog etil-propilena i polieter-sulfona. Ostala pogodna sredstva za presvlačenje mogu biti poliamid, poliimid, poliamidimid, polifenilen-sulfid ili njihove kombinacije.
Da se dalje poboljša stabilnost metalna posuda može imati dio ruba koji se namotava.
Formulacija je pokrenuta odmjernim ventilom koji može isporučiti volumen između 25 μL i 100 μL.
Izbor odmjerenog ventila i tip brtvila će biti proveden prema znanju stručnjaka. Brtvilo može biti od pogodnog elastomernog materijala kao što su polietileni niske gustoće, EPDM, klorpropen i TPE.
Pogodni ventili su komercijalno pristupačni od dobro poznatih proizvođača u aerosolnoj industriji kao primjerice od Valois, Francuska, Bespak plc, UK te 3M-Neotechnic Ltd, UK.
Zbog kemijske stabilnosti lijeka u otopini, preferiano je u nekim slučajevima da su komponente unutarnje površine metalnog ventila koje su u kontaktu sa formulacijom presvučene inertnim materijalom.
Sada korišteni pokretači ventila se općenito mogu koristiti za aerosolne formulacije iz izuma. Kada je potrebna velika količina etanola da se lijek otopi i tako dobiju aerosolni oblaci s optimalnim udjelom koji se udiše, pogodno je koristiti pokretač ventila koji ima otvor promjera između 0.10-0.20 mm (određenije 0.12, 0.14, 0.16 i 0.18 mm).
Ove vrste otvora su pripravljene prema EP prijavi br. 01 130521.6 u ime Prijavitelja.
U nekim slučajevima, a da se stabilizira lijek u otopini, bit će neophodno dobiti aerosolne otopine sa specifičnom očitanom pH koju može odrediti stručnjak prema WO 01/894080.
Hidrofluorugljk kao propelant je preferirano odabran iz skupine HFA 134a, HFA 227 i njihove smjese.
Kootapalo može uključivati jedno ili više otapala, a u drugom slučaju njihov omjer je kritični faktor za učinkovito nastajanje aerosola. Odabir rečenog omjera može biti na bilo koji način proveden od stručnjaka, a na osnovi fizikalno-kemijskih karakteristika razmatranog lijeka.
Preferirana kootapala su obično alkoholi kao što je etanol, propanol, polipropilenglikol, polietilenglikol, gliceril i njihove smjese u ukupnoj količini do 30% w/w, preferirano do 254%, preferiranije do 20% w/w.
Sljedeće korisno kootapalo u nekim vrstama formulacija je voda.
Pogodno je da veličina kapljica bude između oko 0.5 μm i 2.5�μm, što odgovara MMAD od oko 1-2 μm.
Priprava HFA otopine za pMDI
Komplet pMDI posuda je načinjen ručnim stezanjem ventila i naprave za punjenje. Formulacije su pripravljene točnim vaganjem potrebne količine lijeka u metalnu posudu ili bočicu. Dodan je odgovarajući volumen etanola i drugog kootapala ako je potreban u formulaciji. Ventil je pričvršćen na bočicu/metalnu posudu i komplet bočice/metalne posude je podvrgnut sonifikaciji ulktrazvukom kroz 10 minuta. HFA propelant je punjen preko ventila i pMDI je sonificiran ultrazvukom daljnjih 10 minuta. U slučaju da formulacije sadrže samo lijek i propelant, pMDI je sonificiran jedanput, a nakon što je dodan propelant. Konačni sastav je izračunat kao postotak w/v za aktivni sastojak i postotak w/w za kootapalo.
Ispitavanja topljivosti
Ispitivanja topljivosti su provedena u plastikom presvučenim staklenim pMDI bočicama spojenim s kontinuiranim sprej ventilima. Kad je dobivena otopina lijeka u HFA pMDI su čuvani u hladnjaku pri 4 °C (±0.1 °C). pMDI bočice su periodički uklonjene i pomoću polariziranog svjetla je ispitivano da li dolazi do rasta kristala u bočicama.
Ispitivanja prolaska kroz kaskade
Sva ispitivanja prolaska su provedena s formulacijama koje su smještene u anodizirane aluminijske posude snabdjevene ventilima od 50 μL ili 10 μL. Ispitivanja su provedena upotrebom Andersen Cascade Impactor (ACI) snabdjevenog s USP XXII metalnim grlom za ulaz.
ACI je operiran pri brzini protoka od 28.3±2 L min-1. Formulacije HFA otopina su puštene u ACI preko pokretača koji ima otvor promjera od 0.14 do 0.45 mm. Depozicija lijeka na svaku ACI ploču je određena visokotlačnom tekućinskom kromatografijom (HPLC).
MMAD vrijednosti i odgovarajuće geometrijske standardne devijacije (GSD) su izračunate iz krivulja kumulativnog postotka premalih čestica lijeka sakupljenih na svakoj SCI ploči (skala pravih vrijednosti) prema gornjem dijametru za svaku određenu ACI ploči (log10 skala).
Određeni su sljedeći parametri: odmjerena doza koja je suma isporučene doze preko Andersenove aparature plus ostatak aktivnog sastojka deponiran u pokretaču naprave; kumulativna količina aktivnih čestica deponiranih u različitim ACI stupnjevima; količina nakon okretaja; količina u adapteru i grlu (adp/grlo); doza finih čestica ili udahnuta doza (FDP) koja je količina čestica deponirana u stupnjevima 3 na filter ACI i odgovara količini čestica veličina manje od 4.7 μm; udio finih čestica ili udio udahnutih čestica koji predstavlja omjer između udahnute doze i doze isporučene pokretanjem.
Primjeri formulacija prema ovom izumu sadrže sljedeće:
- estere apomorfina u HFA propelantu odabranog od HFA 134a, HFA 227 i njihove smjese i kootapalo odabrano od alkohola, poliola i njihove smjese. U određenoj cjelini formulacija sadrži do 1% w/v diizobutil-apomorfina do 5% w/w etanola, od 0 do 0.1% w/w glicerola i HFA 134a,
- leuprolid-acetat u HFA propelantu odabranog od HFA 134a, HFA 227 i njihove smjese i kootapalo odabrano od alkohola, vode ili njihove smjese. U određenoj cjelini formulacija sadrži do 0.26% w/v leuprolid-acetata, od 15 do 30% w/w etanola, od 2 do 5% w/w vode i HFA 134a.
Primjer 1
Ispitivanja topljivosti diizobutiril-apomorfina, karakteristike aerosolne isporuke i stabilnosti njegovih odgovarajućih pMDI formulacija
Ispitivanja topljivosti
Topljivost diizobutiril-apomorfina je ispitivana pripravom pMDI formulacija s različitim postotkom etanola u HFA 134a ili u HFA 227.
Rezultati pokazuju da su formulacije koje sadrže do 1% w/w diizobutiril-apomorfina topljive u HFA 134a ili u HFA 227.
Ispitivanja karakteristike aerosolne isporuke
Pripravljene su formulacije 0.5% i 1% w/v (250 μg odnosno 500 μg/50 μL) otopine diizobutiril-apomorfina u HFA 134a koje sadrže 5% w/w etanola i 0.1 w/w glicerola. Pripravljene su posude s pokretačem koji ima otvor promjera 0.22 mm.
Određivanje dviju ACI depozicija je provedeno za svaku formulaciju. Dvadeset puta je puštano u ACI.
Formulacije diizobutiril-apomorfina pripravljene prema izumu predstavljaju MMAD oko 2.0 μm, udio finih čestica (FPF) od najmanje 70-75%, dok je količina aktivnih čestica veličine uključene u raspon od 0.43 do 3.3 μm najmanje 60%.
Ispitivanja stabilnosti
Ispitivanja stabilnosti formulacije pripravljene prema Primjeru 1 je započeto čuvanjem prevučenih aluminijskih posuda uspravno i naopako pri 25°C.
Količina izoliranog diizobutiril-apomorfina je određena HPLC.
Nakon šest mjeseci procjenjivanja je izolacija aktivnog sastojka je bila izvrsna i došlo je do minimalne degradacije.
Nije bilo značajne razlike između uspravno i naopako čuvanih posuda.
Primjer 2
Ispitivanja topljivosti leuprolid-acetat, karakteristike aerosolne isporuke i stabilnosti njegovih odgovarajućih pMDI formulacija
Ispitivanja topljivosti
Topljivost leuprolid-acetata je ispitivana prirpavom pMDI formulacija s različitim postotkom etanola i vode u HFA 134a ili u HFA 227.
Rezultati pokazuju da su formulacije koje sadrže do 0.26% w/w leuprolid-acetat topljive u sustavu etanol, voda, HFA 134a.
Kada je dodana voda dobiveno je značajno povećanje topljivosti leuprolid-acetata u sustavu etanol/HFA 134a.
Ispitivanja karakteristike aerosolne isporuke
Pripravljena je formulacija 0.04% w/v (40 μg/100 μL) otopine leuprolid-acetat u HFA 134a koja sadrži 15% w/w etanola i 2% vode. Pripravljene su posude s pokretačem koji ima otvor promjera 0.14 mm.
Određivanje dviju ACI depozicija je provedeno s formulacijom. Dvadeset puta je puštano u ACI.
Formulacija leuprolid-acetat pripravljena prema izumu predstavlja MMAD oko 1.0 μm, udio finih čestica (FPF) od najmanje 72%, dok je količina aktivnih čestica veličine uključene u raspon od 0.43 do 3.3 μm najmanje 61%.
Pripravljena je sljedeća formulacija otopine leuprolid-acetat u HFA 134a koja sadrži 0.08% w/v (80 μg/100 μL) 18% w/w etanola i 3% vode. Pripravljene su posude s pokretačem koji ima otvor promjera 0.14 mm.
Određivanje dviju ACI depozicija je provedeno s formulacijom. Dvadeset puta je puštano u ACI.
Formulacija leuprolid-acetat pripravljena prema izumu predstavlja MMAD oko 1.3 μm, udio finih čestica (FPF) od najmanje 59%, dok je količina aktivnih čestica veličine uključene u raspon od 0.43 do 3.3 μm najmanje 52%.
Ispitivanja stabilnosti
Ispitivanja stabilnosti leuprolida 100 μg/50 mL HFA 134a u pMDI koji sadrži 30% w/w etanola i 5% w/w vode je započeto čuvanjem prevučenih aluminijskih posuda uspravno i naopako pri 25°C.
Sadržaj leuprolid-acetat je određena HPLC.
Nakon šest mjeseci je opažena velika stabilnost.
Claims (16)
1. Farmaceutski aerosolni pripravak koji sadrži otopinu lijeka u smjesi hidrofluoralkanskog propelanta i jednog ili više kootapala, naznačeno time da aerosolne tekuće kapljice isporučene nakon pokretanja inhalatora imaju veličinu čestica između 0.5 μm i 2.5 μm, da je aerodinamički promjer medijalne mase oko 1-2 μm, te da je udio finih čestica najmanje 30%.
2. Farmaceutska formulacija prema patentnom zahtjevu 1, naznačeno time da je koncentracija lijeka najmanje 0.01% w/v.
3. Farmaceutska formulacija prema patentnim zahtjevima 1 do 2, naznačeno time da je koncentracija lijeka najmanje 0.05% w/v.
4. Farmaceutska formulacija prema patentnim zahtjevima 1 do 3, naznačeno time da propelant uključuje jedan ili više HFA odabranih iz sljedeće skupine: HFA 134a i HFA 227.
5. Farmaceutska formulacija prema patentnim zahtjevima 1-4, naznačeno time kootapalo jeste etanol u količini do 30% w/w.
6. Farmaceutska formulacija prema patentnim zahtjevima 1-5, naznačeno time da je kootapalo odabrano iz sljedeće skupine: etanol, niži alkil(C1-C4) alkohol, poliol, polialkilenglikol i njihove kombinacije.
7. Farmaceutska formulacija prema patentnom zahtjevu 6, naznačeno time da su polioli odabrani od sljedećih: glicerol i propilenglikol te polialkilenglikol jeste polietilenglikol.
8. Farmaceutska formulacija prema patentnim zahtjevima 1-5, naznačeno time da je kootapalo (poli)alkoksi-derivat odabran od polialkoksi-alkohola i polioksialkilnih etera i estera.
9. Farmaceutska formulacija prema patentnom zahtjevu 8, naznačeno time da polioksi-alkohol jeste Transcutol®.
10. Farmaceutska formulacija prema patentnom zahtjevu 8, naznačeno time da su polioksialkilnih eteri i esteri odabrani od sljedećih: polioksietilen-alkil-esteri, esteri masnih kiselina te polioksietilen-stearati.
11. Farmaceutska formulacija prema patentnim zahtjevima 1-5, naznačeno time da je kootapalo sadrži ester masne kiseline odabrane od sljedećih: etil-oleat, izorpopil-miristat i izopropil-palmitat.
12. Farmaceutska formulacija prema patentnim zahtjevima 1-6, naznačeno time da je kootapalo sadrži do 10% w/w vode.
13. Farmaceutska formulacija prema bilo kojem od prethodnih patentnih zahtjeva, naznačeno time da je udio finih čestica najmanje 40%.
14. Farmaceutska formulacija prema bilo kojem od prethodnih patentnih zahtjeva, naznačeno time da je udio finih čestica najmanje 50%.
15. Inhalator aerosola koja sadrži formulaciju prijavljenu u bilo kojem od patentnih zahtjeva 1 do 14, naznačeno time da pokretač ventila ima otvor promjera od 0.20 do 0.50 mm.
16. Inhalator aerosola koja sadrži formulaciju prijavljenu u bilo kojem od patentnih zahtjeva 1 do 14, naznačeno time da pokretač ventila ima otvor promjera od 0.10 do 0.20 mm.
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EP02004786A EP1340492A1 (en) | 2002-03-01 | 2002-03-01 | Aerosol formulations for pulmonary administration of medicaments having systemic effects |
PCT/EP2003/001962 WO2003074023A1 (en) | 2002-03-01 | 2003-02-26 | Aerosol formulations for pulmonary administration of medicaments to produce a systemic effect |
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-
2002
- 2002-03-01 EP EP02004786A patent/EP1340492A1/en not_active Withdrawn
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2003
- 2003-02-26 NZ NZ535019A patent/NZ535019A/en unknown
- 2003-02-26 UA UA20040806744A patent/UA81238C2/uk unknown
- 2003-02-26 DE DE60334973T patent/DE60334973D1/de not_active Expired - Lifetime
- 2003-02-26 ES ES03743339T patent/ES2358293T3/es not_active Expired - Lifetime
- 2003-02-26 KR KR10-2004-7012649A patent/KR20040091050A/ko not_active Application Discontinuation
- 2003-02-26 EA EA200401006A patent/EA008571B1/ru not_active IP Right Cessation
- 2003-02-26 AU AU2003215597A patent/AU2003215597B2/en not_active Ceased
- 2003-02-26 PL PL03372261A patent/PL372261A1/xx not_active Application Discontinuation
- 2003-02-26 EP EP03743339A patent/EP1480616B1/en not_active Expired - Lifetime
- 2003-02-26 WO PCT/EP2003/001962 patent/WO2003074023A1/en active Application Filing
- 2003-02-26 CA CA2477879A patent/CA2477879C/en not_active Expired - Fee Related
- 2003-02-26 JP JP2003572543A patent/JP2005519094A/ja active Pending
- 2003-02-26 MX MXPA04008370A patent/MXPA04008370A/es unknown
- 2003-02-26 CN CNA038049775A patent/CN1638731A/zh active Pending
- 2003-02-26 AT AT03743339T patent/ATE488224T1/de active
- 2003-02-26 GE GEAP8390A patent/GEP20063985B/en unknown
- 2003-02-26 IL IL16384203A patent/IL163842A0/xx unknown
- 2003-02-26 US US10/505,679 patent/US20050129621A1/en not_active Abandoned
- 2003-02-26 BR BR0303348-1A patent/BR0303348A/pt not_active IP Right Cessation
- 2003-02-27 TW TW092104190A patent/TW200304833A/zh unknown
- 2003-02-27 CN CNA2009100074339A patent/CN101502500A/zh active Pending
- 2003-02-27 UA UA20040806968A patent/UA80695C2/uk unknown
- 2003-02-28 AR ARP030100686A patent/AR038643A1/es unknown
- 2003-02-28 PE PE2003000200A patent/PE20030949A1/es not_active Application Discontinuation
- 2003-10-31 NO NO20034874A patent/NO20034874L/no not_active Application Discontinuation
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2004
- 2004-08-06 TN TNP2004000148A patent/TNSN04148A1/en unknown
- 2004-08-09 MA MA27816A patent/MA27107A1/fr unknown
- 2004-08-20 HR HRP20040751 patent/HRP20040751A2/hr not_active Application Discontinuation
- 2004-08-31 ZA ZA200406918A patent/ZA200406918B/xx unknown
- 2004-08-31 ZA ZA200406917A patent/ZA200406917B/xx unknown
- 2004-08-31 ZA ZA200406919A patent/ZA200406919B/en unknown
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2015
- 2015-08-19 AR ARP150102671A patent/AR101593A2/es not_active Application Discontinuation
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