HRP920362A2 - Non-chlorofluorocarbon aerosol formulations - Google Patents
Non-chlorofluorocarbon aerosol formulations Download PDFInfo
- Publication number
- HRP920362A2 HRP920362A2 HRP920362A HRP920362A2 HR P920362 A2 HRP920362 A2 HR P920362A2 HR P920362 A HRP920362 A HR P920362A HR P920362 A2 HRP920362 A2 HR P920362A2
- Authority
- HR
- Croatia
- Prior art keywords
- formulation
- drug
- image
- following
- excipient
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims description 43
- 238000009472 formulation Methods 0.000 title claims description 37
- 239000000443 aerosol Substances 0.000 title claims description 20
- 239000003814 drug Substances 0.000 claims description 40
- 229940079593 drug Drugs 0.000 claims description 34
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 claims description 23
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 21
- 239000004094 surface-active agent Substances 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 19
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 12
- 150000004667 medium chain fatty acids Chemical class 0.000 claims description 10
- -1 propylene glycol diester Chemical class 0.000 claims description 10
- KUVIULQEHSCUHY-XYWKZLDCSA-N Beclometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O KUVIULQEHSCUHY-XYWKZLDCSA-N 0.000 claims description 9
- 229950000210 beclometasone dipropionate Drugs 0.000 claims description 9
- WOFMFGQZHJDGCX-ZULDAHANSA-N mometasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(Cl)[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)C(=O)CCl)C(=O)C1=CC=CO1 WOFMFGQZHJDGCX-ZULDAHANSA-N 0.000 claims description 9
- 239000002245 particle Substances 0.000 claims description 8
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 claims description 7
- 229960002744 mometasone furoate Drugs 0.000 claims description 7
- 229960002052 salbutamol Drugs 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 5
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 claims description 4
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003963 antioxidant agent Substances 0.000 claims description 4
- 239000000872 buffer Substances 0.000 claims description 4
- 235000003599 food sweetener Nutrition 0.000 claims description 4
- 239000003765 sweetening agent Substances 0.000 claims description 4
- 208000006673 asthma Diseases 0.000 claims description 3
- KYKAJFCTULSVSH-UHFFFAOYSA-N chloro(fluoro)methane Chemical compound F[C]Cl KYKAJFCTULSVSH-UHFFFAOYSA-N 0.000 claims description 3
- XDRYMKDFEDOLFX-UHFFFAOYSA-N pentamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 XDRYMKDFEDOLFX-UHFFFAOYSA-N 0.000 claims description 3
- 229960004448 pentamidine Drugs 0.000 claims description 3
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 claims description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 2
- BNPSSFBOAGDEEL-UHFFFAOYSA-N albuterol sulfate Chemical compound OS(O)(=O)=O.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 BNPSSFBOAGDEEL-UHFFFAOYSA-N 0.000 claims description 2
- 229940057282 albuterol sulfate Drugs 0.000 claims description 2
- 229960000265 cromoglicic acid Drugs 0.000 claims description 2
- VLARUOGDXDTHEH-UHFFFAOYSA-L disodium cromoglycate Chemical compound [Na+].[Na+].O1C(C([O-])=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C([O-])=O)O2 VLARUOGDXDTHEH-UHFFFAOYSA-L 0.000 claims description 2
- 229960002897 heparin Drugs 0.000 claims description 2
- 229920000669 heparin Polymers 0.000 claims description 2
- 229960001361 ipratropium bromide Drugs 0.000 claims description 2
- KEWHKYJURDBRMN-ZEODDXGYSA-M ipratropium bromide hydrate Chemical compound O.[Br-].O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 KEWHKYJURDBRMN-ZEODDXGYSA-M 0.000 claims description 2
- 229960001317 isoprenaline Drugs 0.000 claims description 2
- IYMMESGOJVNCKV-SKDRFNHKSA-N rimiterol Chemical compound C([C@@H]1[C@@H](O)C=2C=C(O)C(O)=CC=2)CCCN1 IYMMESGOJVNCKV-SKDRFNHKSA-N 0.000 claims description 2
- 229960001457 rimiterol Drugs 0.000 claims description 2
- 229960000195 terbutaline Drugs 0.000 claims description 2
- 239000006068 taste-masking agent Substances 0.000 claims 3
- 239000013543 active substance Substances 0.000 claims 1
- 239000000843 powder Substances 0.000 claims 1
- 239000013589 supplement Substances 0.000 claims 1
- 229920001400 block copolymer Polymers 0.000 description 8
- 239000000969 carrier Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 7
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 6
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 6
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000005642 Oleic acid Substances 0.000 description 6
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 6
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 6
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 229920001213 Polysorbate 20 Polymers 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 5
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 5
- TXGPGHBYAPBDAG-UHFFFAOYSA-N 1,1,2,2,3,3-hexafluoro-4,4-bis(trifluoromethyl)cyclobutane Chemical compound FC(F)(F)C1(C(F)(F)F)C(F)(F)C(F)(F)C1(F)F TXGPGHBYAPBDAG-UHFFFAOYSA-N 0.000 description 4
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- 229920001214 Polysorbate 60 Polymers 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 229940124630 bronchodilator Drugs 0.000 description 4
- YMKDRGPMQRFJGP-UHFFFAOYSA-M cetylpyridinium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 YMKDRGPMQRFJGP-UHFFFAOYSA-M 0.000 description 4
- 229960001927 cetylpyridinium chloride Drugs 0.000 description 4
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- BCCOBQSFUDVTJQ-UHFFFAOYSA-N octafluorocyclobutane Chemical compound FC1(F)C(F)(F)C(F)(F)C1(F)F BCCOBQSFUDVTJQ-UHFFFAOYSA-N 0.000 description 4
- 235000019407 octafluorocyclobutane Nutrition 0.000 description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 4
- 229920000053 polysorbate 80 Polymers 0.000 description 4
- 239000008347 soybean phospholipid Substances 0.000 description 4
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 3
- FFJCNSLCJOQHKM-CLFAGFIQSA-N (z)-1-[(z)-octadec-9-enoxy]octadec-9-ene Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCCCCCCC\C=C/CCCCCCCC FFJCNSLCJOQHKM-CLFAGFIQSA-N 0.000 description 3
- HBXWUCXDUUJDRB-UHFFFAOYSA-N 1-octadecoxyoctadecane Chemical compound CCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCC HBXWUCXDUUJDRB-UHFFFAOYSA-N 0.000 description 3
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 3
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 3
- 239000004147 Sorbitan trioleate Substances 0.000 description 3
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 230000000712 assembly Effects 0.000 description 3
- 238000000429 assembly Methods 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000004359 castor oil Substances 0.000 description 3
- 235000019438 castor oil Nutrition 0.000 description 3
- DTPCFIHYWYONMD-UHFFFAOYSA-N decaethylene glycol Polymers OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO DTPCFIHYWYONMD-UHFFFAOYSA-N 0.000 description 3
- 229940044949 eucalyptus oil Drugs 0.000 description 3
- 239000010642 eucalyptus oil Substances 0.000 description 3
- 125000005456 glyceride group Chemical group 0.000 description 3
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229940041616 menthol Drugs 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 150000004666 short chain fatty acids Chemical class 0.000 description 3
- 235000021391 short chain fatty acids Nutrition 0.000 description 3
- 235000019337 sorbitan trioleate Nutrition 0.000 description 3
- 229960000391 sorbitan trioleate Drugs 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 150000003626 triacylglycerols Chemical class 0.000 description 3
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical compound C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 239000000168 bronchodilator agent Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000009931 harmful effect Effects 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- BHIZVZJETFVJMJ-UHFFFAOYSA-N 2-hydroxypropyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCC(C)O BHIZVZJETFVJMJ-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 239000004341 Octafluorocyclobutane Substances 0.000 description 1
- 229920002048 Pluronic® L 92 Polymers 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 229920002359 Tetronic® Polymers 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000004004 anti-anginal agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000007883 bronchodilation Effects 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- PWEOPMBMTXREGV-UHFFFAOYSA-N decanoic acid;octanoic acid;propane-1,2-diol Chemical compound CC(O)CO.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCCCC(O)=O.CCCCCCCCCC(O)=O PWEOPMBMTXREGV-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 229910001651 emery Inorganic materials 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 230000007407 health benefit Effects 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229940039009 isoproterenol Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960002969 oleic acid Drugs 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 229940026235 propylene glycol monolaurate Drugs 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Description
Uvod Introduction
Sadašnji izum se odnosi na formulacije aerosola koje bitno ne sadrže klorofluorougljične (CFC) spojeve. Formulacije aerosola prema izumu imaju širok spektar primjene, a jedno od područja je i primjena u medicini, naročito u presuriziranim inhalatorima za davanje odmjerenih doza (MDI). The present invention relates to aerosol formulations substantially free of chlorofluorocarbon (CFC) compounds. Aerosol formulations according to the invention have a wide range of applications, and one of the areas is application in medicine, especially in pressurized metered dose inhalers (MDIs).
Inhalatori za davanje odmjerenih doza su se pokazali kao efikasan način za oralno i nazalno davanje lijekova. Široko su korišteni za davanje bronhodilatatorskih i steroidnih spojeva astmatičarima, a mogu se koristiti i za davanje drugih spojeva kao što su pentamidin i antiinflamatorni lijekovi koji nemaju bronhodilatatorsko djelovanje. Brz početak djelovanja i odsustvo bilo kakvih značajnijih sporednih efekata doveli su do formuliranja velikog broja lijekova za ovakav način davanja. Lijek se pacijentu tipično daje uz korištenje nosivog sustava koji u načelu sadrži jedan ili više nosača sa odgovarajućim naponom pare, pogodnih za oralno ili nazalno davanje. Poželjniji nosivi sustavi tipično sadrže nosač 11, nosač 12, nosač 114, ili njihove smjese. Često se napon pare nosivog sustava podešava tako što se nosaču dodaje neki tekući ekscipijent. Metered dose inhalers have proven to be an efficient way to administer drugs orally and nasally. They are widely used to administer bronchodilator and steroid compounds to asthmatics, and can also be used to administer other compounds such as pentamidine and anti-inflammatory drugs that do not have a bronchodilator effect. The quick onset of action and the absence of any significant side effects led to the formulation of a large number of drugs for this method of administration. The drug is typically administered to the patient using a carrier system that, in principle, contains one or more carriers with appropriate vapor pressure, suitable for oral or nasal administration. More preferred carrier systems typically include carrier 11, carrier 12, carrier 114, or mixtures thereof. Often the vapor pressure of the carrier system is adjusted by adding some liquid excipient to the carrier.
Nosači 11, 12 i 114, međutim, pripadaju klasi spojeva poznatih kao klorofluorougljični spojevi, koji su povezani sa nestankom ozona u atmosferi. Smatra se da ozon blokira izvjesna štetna ultraljubičasta zračenja, pa će smanjenje količine ozona u atmosferi dovesti po povećanog broja slučajeva raka kože. Sedamdesetih godina su poduzeti izvjesni koraci da se smanji otpuštanje CFC spojeva koji potiču iz aerosola. Korišteni su drugi nosači, kao što su ugljikovodici, ili je proizvod davan na drugi način. Obzirom daje korištenje CFC spojeva u medicinskim primjenama relativno malo, tj. predstavlja manje od 1% ukupnog otpuštanja CFC spoja, kao i s obzirom na zdravstvene prednosti koje se postižu korištenjem inhalatora za davanje odmjerenih doza, u to vrijeme nisu poduzeti koraci da se ograniči primjena CFC spojeva u inhalatorima za davanje odmjerenih doza. Kontinuirano i sve preciznije mjerenje ozona je, međutim, pokazalo da ranija ograničenja u upotrebi CFC nisu dovoljna, pa bi za drastično smanjenje otpuštanja CFC trebalo poduzeti dodatne značajne mjere. Nedavno su dane preporuke da bi proizvodnja CFC trebala praktički prestati do kraja ovog stoljeća. Rezultat je da u srednjoročnom i dugoročnom periodu neće biti moguće nastaviti sa upotrebom CFC. Iako su činjeni izvjesni napori da se koriste inhalatori za davanje odmjerene doze koji nisu pod pritiskom, veći dio ovakvih sprava nije se pokazao sasvim uspješnim. Mnogi od njih ne daju ravnomjerne doze, mehanički su komplicirani, ne osiguravaju 100-200 doza po bočici aerosola, pojedinac ih teško koristi, glomazni su i/ili nezgodni za upotrebu, naročito kada pacijent ima akutnu potrebu za lijekom. Carriers 11, 12 and 114, however, belong to a class of compounds known as chlorofluorocarbon compounds, which are linked to the depletion of ozone in the atmosphere. Ozone is thought to block certain harmful ultraviolet radiations, so a decrease in the amount of ozone in the atmosphere will lead to an increased number of skin cancer cases. In the 1970s, certain steps were taken to reduce the release of CFC compounds originating from aerosols. Other carriers, such as hydrocarbons, were used, or the product was administered in another way. Given that the use of CFC compounds in medical applications is relatively small, i.e. representing less than 1% of the total release of CFC compounds, and given the health benefits achieved by using metered dose inhalers, no steps were taken at that time to limit the use of CFCs compounds in metered dose inhalers. However, the continuous and increasingly precise measurement of ozone has shown that the previous restrictions on the use of CFCs are not sufficient, so additional significant measures should be taken to drastically reduce the release of CFCs. Recommendations have recently been made that CFC production should virtually cease by the end of this century. The result is that in the medium and long term it will not be possible to continue using CFCs. Although some efforts have been made to use non-pressurized metered dose inhalers, most such devices have not been entirely successful. Many of them do not give uniform doses, are mechanically complicated, do not provide 100-200 doses per aerosol bottle, are difficult for an individual to use, are bulky and/or inconvenient to use, especially when the patient has an acute need for medicine.
Kao rezultat, javlja se potreba za formulacijama aerosola koje su bitno bez CFC. Nosači koji ne sadrže CFC trebaju zadovoljiti nekoliko kriterija koji se postavljaju kod presuriziranih inhalatora za davanje odmjerene doze. Trebaju biti netoksični, stabilni i da ne reagiraju s lijekom ili drugim glavnim komponentama u ventilu/pobuđivaču. Jedan od nosača koji su se pokazali kao pogodnije i CF3-CH2F, poznat i kao Freon 134a, HFA 134a, HFC 134a, ili 1,1,1,2-tetrafluoroetan. Međutim, fizičke osobine, tj. napon pare, polarnost, topivost, Gustina i viskozitet HFC 134a razlikuju se od osobina obično korištenih nosača. Nosač HFC 134a ima napon pare od 5.84 x 105 N/m2 apsolutnih, što je suviše visoka vrijednost za korištenje u inhalatorima za davanje odmjerene doze. Osim toga, obično korištena površinski aktivna sredstva mogu biti netopiva u HFC 134a. Nadalje, kada lijek treba davati u otopini, lijek ne mora biti lako topiv u ovom nosaču. Razlike u gustoći i polarnosti između HFC 134a i ranije korištenih CFC nosača mogu uzrokovati različito davanje lijeka kada se CFC nosač zamijeni sa HFC 134a. Lijekovi se mogu pretvoriti u pastu, da se talože ili aglomeriraju u nosaču različitom od CFC, čak i ako do takvih pojava nije dolazilo u CPC nosaču. As a result, there is a need for aerosol formulations that are substantially CFC-free. Carriers that do not contain CFCs should meet several criteria set for pressurized metered dose inhalers. They should be non-toxic, stable and non-reactive with the drug or other major components in the valve/actuator. One of the carriers that proved to be more suitable is CF3-CH2F, also known as Freon 134a, HFA 134a, HFC 134a, or 1,1,1,2-tetrafluoroethane. However, the physical properties, i.e. vapor pressure, polarity, solubility, density and viscosity of HFC 134a differ from those of commonly used carriers. The HFC 134a carrier has a vapor pressure of 5.84 x 105 N/m2 absolute, which is too high for use in metered dose inhalers. In addition, commonly used surfactants may be insoluble in HFC 134a. Furthermore, when the drug is to be administered in solution, the drug need not be readily soluble in this carrier. Differences in density and polarity between HFC 134a and previously used CFC carriers may cause different drug delivery when the CFC carrier is replaced with HFC 134a. Medicines can turn into a paste, settle or agglomerate in a carrier other than CFC, even if such phenomena did not occur in a CPC carrier.
Korištenje HFA 134a u medicinskim inhalatorima je već opisano u znanosti. Europski patent Br. 0 372 777 odnosi se na medicinske formulacije aerosola koje sadrže Freon 134a i ađuvant koji ima veću polarnost nego nosač. U ovoj publikaciji nabrojano je nekoliko mogućih ađuvanata i površinski aktivnih sredstava koja se mogu koristiti u kombinaciji s nosačem i lijekom. The use of HFA 134a in medical inhalers has already been described in science. European patent No. 0 372 777 relates to medical aerosol formulations containing Freon 134a and an adjuvant having a higher polarity than the carrier. This publication lists several possible adjuvants and surfactants that can be used in combination with the carrier and drug.
Međunarodna patentna prijava Br. WO 91/04011 opisuje kombinaciju 1,1,1,2-tetrafluoroetana i sprašenog lijeka koji je obložen neperfluoriranim površinski aktivnim sredstvom prije nego što je sprašeni lijek dispergiran u nosaču. Na str. 6-7 ove publikacije nabrojana su površinski aktivna sredstva pogodna za korištenje s nosačem. Po potrebi može se dodati i perfluorirani ađuvant. Prethodno oblaganje lijeka, međutim, ne mora imati prednosti, jer predstavlja dodatni, komplicirani stupanj u postupku proizvodnje. International patent application No. WO 91/04011 describes a combination of 1,1,1,2-tetrafluoroethane and a powdered drug which is coated with a non-perfluorinated surfactant before the powdered drug is dispersed in a carrier. On p. 6-7 of this publication list surfactants suitable for use with a carrier. If necessary, a perfluorinated adjuvant can be added. Pre-coating the drug, however, does not necessarily have advantages, as it represents an additional, complicated step in the production process.
Izvještaj o ispitivanju Br. 30161 iz svibnja 1989. godine navodi da nosači različiti od CFC, kao što su fluorirani ugljikovodici, mogu se koristiti za presurizirane lijekove koji se daju direktno u pluća, na primjer za bronhodilatatore. Američki patent Br. 4,174,295 opisuje kombinaciju HFC 134a s različitim kloriranim ugljikovodicima i, po potrebi, s zasićenim ugljikovodikom. Test report No. 30161 of May 1989 states that carriers other than CFCs, such as fluorocarbons, can be used for pressurized drugs that are delivered directly to the lungs, for example bronchodilators. US Patent No. 4,174,295 describes the combination of HFC 134a with various chlorinated hydrocarbons and, if necessary, with a saturated hydrocarbon.
Američki patent Br. 2,885,427 opisuje korištenje HFC-134a kao nosača za aerosol. Američki patent Br. 3,261,748 opisuje korištenje HFC-134a za anesteziju. US Patent No. 2,885,427 describes the use of HFC-134a as an aerosol carrier. US Patent No. 3,261,748 describes the use of HFC-134a for anesthesia.
Američki patenti Br. 4,129,603, 4,311,863, 4,851,595 i Europski patent Br. 379,793 također opisuju korištenje HFC-134a kao nosača za aerosol. US Patent No. 4,129,603, 4,311,863, 4,851,595 and European Patent No. 379,793 also describes the use of HFC-134a as an aerosol carrier.
Konkretne gore opisane kombinacije ne moraju, međutim, osigurati željenu topivost, stabilnost, nisku toksičnost, točno doziranje, odgovarajuću veličinu čestica (ako se radi o suspenziji) i/ili kompatibilnost s uobičajenim ventilskim sklopovima koji se koriste za inhalatore za davanje odmjerene doze. The particular combinations described above may not, however, provide the desired solubility, stability, low toxicity, accurate dosing, appropriate particle size (if a suspension) and/or compatibility with conventional valve assemblies used for metered dose inhalers.
Opis izuma Description of the invention
Sadašnji izum se odnosi na netoksične formulacije koje bitno ne sadrže CFC spojeve, koje izražavaju poboljšanu stabilnost i kompatibilnost s lijekovima i ventilskim sklopovima i koji se relativno lako proizvode. The present invention relates to non-toxic formulations which are substantially free of CFC compounds, which exhibit improved stability and compatibility with drugs and valve assemblies, and which are relatively easy to manufacture.
Sadašnji izum se također odnosi i na formulacije koje se mogu koristiti u postojećim uređajima za punjenje aerosola, sa samo relativno malim izmjenama i bez potrebe za prethodnim oblaganjem lijeka. The present invention also relates to formulations that can be used in existing aerosol filling devices, with only relatively minor modifications and without the need for prior drug coating.
Izum obuhvaća formulaciju aerosola koja sadrži: The invention includes an aerosol formulation containing:
A. efikasnu količinu lijeka; i A. effective amount of medicine; and
B. 1,1,1,2-tetrafluoroetan. B. 1,1,1,2-tetrafluoroethane.
Formulacija može, po potrebi, sadržavati i ekscipijent koji je poželjno izabran iz skupine koja obuhvaća: propilen glikolne diestere masnih kiselina s lancem srednje dužine; trigliceridne estere masnih kiselina s lancem srednje dužine; perfluorodimetilciklobutan; perfluorociklobutan; polietilen glikol; mentol; lauroglikol; dietilen glikol monoetileter; poliglikolizirane gliceride masnih kiselina s lancem srednje dužine; alkohole; eukaliptusovo ulje; masne kiseline kratkog lanca; i njihove kombinacije. The formulation can, if necessary, also contain an excipient which is preferably chosen from the group that includes: propylene glycol diesters of fatty acids with a medium chain length; triglyceride esters of fatty acids with a medium chain length; perfluorodimethylcyclobutane; perfluorocyclobutane; polyethylene glycol; menthol; lauroglycol; diethylene glycol monoethyl ether; polyglycolized glycerides of medium-chain fatty acids; alcohols; eucalyptus oil; short chain fatty acids; and their combinations.
Formulacija može, po potrebi, dalje sadržavati i površinski aktivno sredstvo. Površinski aktivna sredstva su poželjno izabrana iz skupine koja obuhvaća: oleinsku kiselinu; sorbitan trioleat; cetil piridinij klorid; sojin lecitin; polioksietilen(20) sorbitan monolaurat; polioksietilen(20) sorbitan monostearat; polioksietilen(20) sorbitan monooleat; polioksi-propilen-polioksietilenske blok kopolimere; polioksietilen(10) stearil eter; polioksietilen(2) oleil eter; polioksipropilen-polioksietilen-etilendiaminske blok kopolimere; etoksilat ricinusovog ulja; i njihove smjese. The formulation can, if necessary, further contain a surfactant. Surfactants are preferably selected from the group comprising: oleic acid; sorbitan trioleate; cetyl pyridinium chloride; soy lecithin; polyoxyethylene(20) sorbitan monolaurate; polyoxyethylene(20) sorbitan monostearate; polyoxyethylene(20) sorbitan monooleate; polyoxy-propylene-polyoxyethylene block copolymers; polyoxyethylene(10) stearyl ether; polyoxyethylene(2) oleyl ether; polyoxypropylene-polyoxyethylene-ethylenediamine block copolymers; castor oil ethoxylate; and their mixtures.
Poželjni tekući ekscipijenti su dietilen glikol monoetileter, propilen glikolni diesteri masnih kiselina s lancem srednje dužine, perfluorodimetilciklobutan i polietilen glikol. Preferred liquid excipients are diethylene glycol monoethyl ether, propylene glycol diesters of medium chain fatty acids, perfluorodimethylcyclobutane, and polyethylene glycol.
Poželjna površinski aktivna sredstva su oleinska kiselina, sorbitan trioleat, cetilpiridinij klorid, polioksietilen(20) sorbitan monolaurat, polioksipropilen-polioksietilenski blok kopolimeri, sojin lecitin i polioksipropilen-poliolksietilen-etilendiaminski blok kopolimeri, pri čemu je naročito poželjna oleinska kiselina. Preferred surfactants are oleic acid, sorbitan trioleate, cetylpyridinium chloride, polyoxyethylene(20) sorbitan monolaurate, polyoxypropylene-polyoxyethylene block copolymers, soy lecithin and polyoxypropylene-polyoxyethylene-ethylenediamine block copolymers, with oleic acid being particularly preferred.
Izum je naročito koristan kada se koristi za lijekove kao što su albuterol, mometasone furoat ili beklometazon dipropionat, kao i njihove soli i klatrati. The invention is particularly useful when used for drugs such as albuterol, mometasone furoate or beclomethasone dipropionate, as well as their salts and clathrates.
Sastav formulacije je u sljedećem opsegu: The composition of the formulation is in the following scope:
A. 1,1,1,2-tetrafluoroetan 25 - 99.99 mas.% A. 1,1,1,2-tetrafluoroethane 25 - 99.99 wt.%
B. lijek 0.01 - 1 mas.% B. drug 0.01 - 1 wt.%
C. ekscipijent 0 - 75 mas.% C. excipient 0 - 75 wt.%
D. površinski aktivno sredstvo 0-3 mas.% D. surfactant 0-3 wt.%
Sadašnji izum se također odnosi na metodu za tretiranje astme kod sisavaca, koji se sastoji u davanju, sisavcu kome je takav tretman potreban, efikasne količine formulacije aerosola koja sadrži: The present invention also relates to a method for treating asthma in mammals, which consists in administering to a mammal in need of such treatment an effective amount of an aerosol formulation containing:
A. lijek izabran iz skupine koja obuhvaća albuterol, mometasone furoat, beklometazon dipropionat, kao i njihove soli i klatrate; A. a drug selected from the group comprising albuterol, mometasone furoate, beclomethasone dipropionate, as well as their salts and clathrates;
B. 1,1,1,2-tetrafloroetan; i B. 1,1,1,2-tetrafluoroethane; and
C. po potrebi ekscipijent, poželjno izabran iz skupine koja obuhvaća propilen glikolne diestere masnih kiselina s lancem srednje dužine; trigliceridne estere masnih kiselina s lancem srednje dužine; perfluorodimetilciklobutan; perfluorociklobutan; polietilen glikol; mentol; lauroglikol; dietilen glikol monoetileter; poliglikolizirane gliceride masnih kiselina s lancem srednje dužine; alkohole; eukaliptusovo ulje; masne kiseline kratkog lanca; i njihove kombinacije. C. if necessary, an excipient, preferably selected from the group comprising propylene glycol diesters of fatty acids with a medium chain length; triglyceride esters of fatty acids with a medium chain length; perfluorodimethylcyclobutane; perfluorocyclobutane; polyethylene glycol; menthol; lauroglycol; diethylene glycol monoethyl ether; polyglycolized glycerides of medium-chain fatty acids; alcohols; eucalyptus oil; short chain fatty acids; and their combinations.
Površinski aktivno sredstvo je prisutno po potrebi. Ono je poželjno izabrano iz skupine koja obuhvaća oleinsku kiselinu; sorbitan trioleat; cetil piridinij klorid; sojin lecitin; polioksietilen(20) sorbitan monolaurat; polioksietilen(20) sorbitan monostearat; polioksietilen(20) sorbitan monooleat; polioksi-propilen-polioksietilenske blok kopolimere; polioksietilen(10) stearil etar; polioksietilen(2) oleil etar; polioksipropilen-polioksietilen-etilendiaminske blok kopolimere; etoksilat ricinusovog ulja; i njihove smjese. Surfactant is present as needed. It is preferably selected from the group comprising oleic acid; sorbitan trioleate; cetyl pyridinium chloride; soy lecithin; polyoxyethylene(20) sorbitan monolaurate; polyoxyethylene(20) sorbitan monostearate; polyoxyethylene(20) sorbitan monooleate; polyoxy-propylene-polyoxyethylene block copolymers; polyoxyethylene(10) stearyl ether; polyoxyethylene(2) oleyl ether; polyoxypropylene-polyoxyethylene-ethylenediamine block copolymers; castor oil ethoxylate; and their mixtures.
Sve formulacije iz sadašnjeg izuma koriste nosač 134a u kombinaciji s lijekom, po potrebi s tekućim ekscipijentom i po potrebi s površinski aktivnim sredstvom. Ekscipijent potpomaže kompatibilnost lijeka s nosačem i također snižava pritisak pod kojim se formulacjia daje do podnošljivog opsega, tj. do oko 2.76 - 5.52 x 105 N/m2 apsolutnih, poželjno 3.45 - 4.83 x 105 N/m2. Izabrani ekscipijent ne smije biti reaktivan s lijekom, treba biti relativno netoksičan i imati napon pare ispod oko 3.45 x 105 N/m2 apsolutnih. Izraz "masne kiseline s srednjom dužinom lanca", kako se koristi u ovom tekstu, označava lance alkil skupina koji se završavaju skupinom -COOH i imaju 6-12 ugljikovih atoma, poželjno 8-10 ugljikovih atoma. Izraz "masne kiseline kratkog lanca" odnosi se na lance alkil skupina koji se završavaju skupinom -COOH i imaju 4-8 ugljikovih atoma. Izraz "alkohol" obuhvaća C1-3alkohole kao što su metanol, etanol i izopropanol. Među poželjnim ekscipijentima su sljedeći: All formulations of the present invention utilize carrier 134a in combination with a drug, optionally with a liquid excipient, and optionally with a surfactant. The excipient aids the compatibility of the drug with the carrier and also lowers the pressure under which the formulation is administered to a tolerable range, ie to about 2.76 - 5.52 x 105 N/m2 absolute, preferably 3.45 - 4.83 x 105 N/m2. The selected excipient should not be reactive with the drug, should be relatively non-toxic and have a vapor pressure below about 3.45 x 105 N/m2 absolute. The term "medium chain fatty acids", as used herein, refers to chains of alkyl groups ending in -COOH and having 6-12 carbon atoms, preferably 8-10 carbon atoms. The term "short-chain fatty acids" refers to chains of alkyl groups ending in -COOH and having 4-8 carbon atoms. The term "alcohol" includes C1-3 alcohols such as methanol, ethanol and isopropanol. Among the preferred excipients are the following:
propilen glikolni diesteri masnih kiselina s lancem srednje dužine, koji se nabavljaju pod trgovačkim nazivom Miglyol 840 (Hüls America, Inc., Piscataway, N.J); propylene glycol diesters of medium chain fatty acids, available under the trade name Miglyol 840 (Hüls America, Inc., Piscataway, N.J);
trigliceridni esteri masnih kiselina s lancem srednje dužine, koji se nabavljaju pod trgovačkim nazivom Miglyol 812 (Hüls); triglyceride esters of fatty acids with a medium chain length, which are available under the trade name Miglyol 812 (Hüls);
perfluorodimetilciklobutan, koji se nabavlja pod trgovačkim nazivom Vertrel 245 (E.I. DuPont de Nemours & Co. Inc., Wilmington, Delaware); perfluorodimethylcyclobutane, which is available under the trade name Vertrel 245 (E.I. DuPont de Nemours & Co. Inc., Wilmington, Delaware);
perfluorociklobutan, koji se nabavlja pod trgovačkim nazivom oktafluoro ciklobutan (PCR Gainsville, Florida); polietilen glikol, koji se nabavlja pod trgovačkim nazivom PEG 40 (BASF, Parsippany, N.J.); perfluorocyclobutane, which is available under the trade name octafluorocyclobutane (PCR Gainsville, Florida); polyethylene glycol, available under the trade name PEG 40 (BASF, Parsippany, N.J.);
mentol (Pluess-Stauffer International Stanford, Connecticut); menthol (Pluess-Stauffer International Stanford, Connecticut);
propilen glikol monolaurat, koji se nabavlja pod trgovačkim nazivom lauroglycol (Gattefossé Elmsford, N.Y.); propylene glycol monolaurate, which is available under the trade name lauroglycol (Gattefossé Elmsford, N.Y.);
dietilen glikol monoetiletar, koji se nabavlja pod trgovačkim nazivom Transcutol (Gattefossé); diethylene glycol monoethylether, which is available under the trade name Transcutol (Gattefossé);
poliglikolizirani gliceridi masnih kiselina s lancem srednje dužine, koji se nabavljaju pod trgovačkim nazivom Labrafac Hydro WL 1219 (Gattefossé); polyglycolized glycerides of medium-chain fatty acids, which are available under the trade name Labrafac Hydro WL 1219 (Gattefossé);
alkoholi, kao što je etanol, metanol ili izopropanol; alcohols, such as ethanol, methanol or isopropanol;
eukaliptusovo ulje (Pluess-Stauffer International); i njihove smjese. eucalyptus oil (Pluess-Stauffer International); and their mixtures.
Radi snižavanja površinskih i međupovršinskih napona između lijeka i nosača, po potrebi može se dodati i površinski aktivno sredstvo. Kada lijek, nosač i ekscipijent trebaju graditi suspenziju, površinski aktivno sredstvo može ali i ne mora biti potrebno. Kada lijek, nosač i ekscipijent trebaju graditi otopinu, površinski aktivno sredstvo može biti potrebno ili nepotrebno, djelomično u ovisnosti o topivosti konkretnog lijeka i ekscipijenta. Površinski aktivno sredstvo može biti bilo koji pogodan, netoksični spoj koji nije reaktivan s lijekom i koji značajnije snižava površinski napon između lijeka, ekscipijenta i nosača i/ili djeluje kao sredstvo za podmazivanje ventila. Među poželjnim površinski aktivnim sredstvima su: In order to lower the surface and interfacial tensions between the drug and the carrier, a surface-active agent can be added if necessary. When the drug, carrier and excipient need to form a suspension, a surfactant may or may not be necessary. When the drug, carrier and excipient need to form a solution, a surfactant may or may not be necessary, depending in part on the solubility of the particular drug and excipient. The surfactant can be any suitable, non-toxic compound that is not reactive with the drug and that significantly lowers the surface tension between the drug, excipient and carrier and/or acts as a valve lubricant. Among the preferred surfactants are:
oleinska kiselina, koja se nabavlja pod trgovačkim nazivom oleinska kiselina NF6321 (Henkel Corp. Emery Group, Cincinnati, Ohio); oleic acid, which is available under the trade name oleic acid NF6321 (Henkel Corp. Emery Group, Cincinnati, Ohio);
cetilpiridinijum klorid (Arrow Chemical, Inc. Westwood, N.J.); cetylpyridinium chloride (Arrow Chemical, Inc. Westwood, N.J.);
sojin lecitin, koji se nabavlja pod trgovačkim nazivom Epikuron 200 (Lucas Meyer Decatur, Illinois); soy lecithin, available under the trade name Epikuron 200 (Lucas Meyer Decatur, Illinois);
polioksietilen(10) stearil eter, koji se nabavlja pod trgovačkim nazivom Briji 76 (Imperial Chemical Industries - ICI); polyoxyethylene(10) stearyl ether, which is purchased under the trade name Briji 76 (Imperial Chemical Industries - ICI);
polioksietilen(2) oleil eter, koji se nabavlja pod trgovačkim nazivom Briji 92 (ICI); polyoxyethylene(2) oleyl ether, which is available under the trade name Briji 92 (ICI);
polioksipropilen-polioksietilen-etilendiaminski blok kopolimer, koji se nabavlja pod trgovačkim nazivom Tetronic 150 R1 (BASF); polyoxypropylene-polyoxyethylene-ethylenediamine block copolymer, which is available under the trade name Tetronic 150 R1 (BASF);
polioksietilen(20) sorbitan monolaurat, koji se nabavlja pod trgovačkim nazivom Tween 20 (ICI Specialty Chemicals, Wilmington, Delaware); polyoxyethylene(20) sorbitan monolaurate, which is available under the trade name Tween 20 (ICI Specialty Chemicals, Wilmington, Delaware);
polioksietilen(20) sorbitan monostearat, koji se nabavlja pod trgovačkim nazivom Tween 60 (ICI); polyoxyethylene(20) sorbitan monostearate, which is available under the trade name Tween 60 (ICI);
polioksietilen(20) sorbitan monooleat, koji se nabavlja pod trgovačkim nazivom Tween 80 (ICI); polyoxyethylene(20) sorbitan monooleate, which is available under the trade name Tween 80 (ICI);
polioksipropilen-polioksietilenski blok kopolimeri, koji se nabavljaju pod trgovačkim nazivima Pluronic L-92, Pluronic L-121 i Pluronic F 68 (BASF); polyoxypropylene-polyoxyethylene block copolymers, which are available under the trade names Pluronic L-92, Pluronic L-121 and Pluronic F 68 (BASF);
etoksilat ricinusovog ulja, koji se nabavlja pod trgovačkim nazivom Alkasurf CO-40 (Rhone-Poulenc Mississauga Ontario, Canada); i njihove smjese. castor oil ethoxylate, which is available under the trade name Alkasurf CO-40 (Rhone-Poulenc Mississauga Ontario, Canada); and their mixtures.
Lijekovi koji se koriste prema sadašnjem izumu obuhvaćaju svaki farmaceutski aktivni spoj koji treba davati oralnom inhalacijom ili nazalno. Tipične klase spojeva obuhvaćaju bronhodilatatore, antiinflamatorne spojeve, antihistaminike, antialergene, analgetike, antitusike, anti-anginalne lijekove, steroide, kortikosteroide, vazokonstriktore i antibiotike. Konkretni spojevi unutar ovih klasa su albuterol, mometasone furoat, beklometazon dipropionat, izoproterenol, heparin, terbutalin, rimiterol, perbuterol, dinatrij kromoglikat, izoprenalin, adrenalin, pentamidin i ipratropium bromid. Ovi spojevi se mogu koristiti bilo kao slobodne baze, kao soli ili kao klatrati, u ovisnosti o stabilnosti i topivosti aktivnog spoja u konkretnoj formulaciji. Kada se koriste klatrati, naročito su poželjni P-11 i heksanski klatrati. The medicaments used according to the present invention include any pharmaceutically active compound to be administered by oral inhalation or nasal administration. Typical classes of compounds include bronchodilators, anti-inflammatory compounds, antihistamines, antiallergens, analgesics, antitussives, anti-anginal drugs, steroids, corticosteroids, vasoconstrictors, and antibiotics. Specific compounds within these classes are albuterol, mometasone furoate, beclomethasone dipropionate, isoproterenol, heparin, terbutaline, rimiterol, perbuterol, disodium cromoglycate, isoprenaline, adrenaline, pentamidine, and ipratropium bromide. These compounds can be used either as free bases, as salts or as clathrates, depending on the stability and solubility of the active compound in the particular formulation. When clathrates are used, P-11 and hexane clathrates are particularly preferred.
Kada aktivni spoj gradi suspenziju, veličina čestica treba biti relativno ravnomjerna, pri čemu će sve čestice bitno biti u opsegu od oko 0.1 do 25 μm, poželjno od 0.5 do 10 μm i najbolje od 1 do 5 μm. Čestice veće od 25 μm mogu se zadržavati u orofaringalnoj šupljini, dok čestice manje od oko 0.5 μm ne treba koristiti jer će vjerojatno biti izdahnute i neće doprijeti do pacijentovih pluća. When the active compound forms a suspension, the particle size should be relatively uniform, whereby all particles will essentially be in the range of about 0.1 to 25 μm, preferably from 0.5 to 10 μm and preferably from 1 to 5 μm. Particles larger than 25 μm can be retained in the oropharyngeal cavity, while particles smaller than about 0.5 μm should not be used because they will probably be exhaled and will not reach the patient's lungs.
Formulacije iz sadašnjeg izuma mogu se puniti u posude za aerosol korištenjem uobičajene opreme za punjenje. S obzirom da nosač 134a može ne biti kompatibilan sa svim elastomernim spojevima koji se u današnje vrijeme koriste u ventilskim sklopovima za aerosole, možda će biti potrebno da se koriste drugi materijali, kao što je bijela butadienska gruma, ili da se koriste ekscipijenti i, po potrebi, površinski aktivna sredstva koja ublažavaju štetno djelovanje nosača 134a na ventilske komponente. Po potrebi može se koristiti i pobudni mehanizam sa odstojnikom, kako bi se reducirala sila raspršenog mlaza iz MDI. The formulations of the present invention can be filled into aerosol containers using conventional filling equipment. Since carrier 134a may not be compatible with all elastomeric compounds currently used in aerosol valve assemblies, it may be necessary to use other materials, such as white butadiene gum, or to use excipients and, if necessary, surfactants that mitigate the harmful effect of the carrier 134a on the valve components. If necessary, an excitation mechanism with a spacer can be used, in order to reduce the force of the sprayed jet from the MDI.
Da bi se osiguralo ravnomjerno dispergiranje aktivnog sastojka, formulacije tipično sadrže sljedeće sastojke: To ensure even dispersion of the active ingredient, formulations typically contain the following ingredients:
[image] [image]
U ovisnosti o konkretnoj primjeni, posuda može biti napunjena s unaprijed određenom količinom formulacije za jedno ili za više davanja. Tipično je kontejner predviđen za višestruko davanje, pa je veoma važno da se formulacija daje podjednako u svakoj dozi. Na primjer, kada formulacija služi za bronhodilataciju, kontejner je tipično napunjen količinom koja je dovoljna za 200 doza. Depending on the specific application, the container can be filled with a predetermined amount of the formulation for one or more administrations. Typically, the container is intended for multiple administration, so it is very important that the formulation is administered equally in each dose. For example, when the formulation is for bronchodilation, the container is typically filled with an amount sufficient for 200 doses.
Pogodne suspenzije mogu se djelomično odrediti promatranjem nekoliko fizičkih osobina, tj. brzine aglomeracije čestica, veličine aglomerata i brzine formiranja paste i taloženja čestica, nakon čega će se ovi parametri usporediti s nekim prihvatljivim standardom. Pogodne otopine mogu se odrediti promatranjem topivosti lijeka u cijelom temperaturnom opsegu koji je preporučen za skladištenje. Suitable suspensions can be partially determined by observing several physical properties, i.e. particle agglomeration rate, agglomerate size and rate of paste formation and particle settling, after which these parameters will be compared with some acceptable standard. Suitable solutions can be determined by observing the solubility of the drug throughout the temperature range recommended for storage.
Suspenzije prema sadašnjem izumu mogu se poželjno dobiti bilo punjenjem pod pritiskom ili punjenjem na niskoj temperaturi, pri čemu su oba ova postupka dobro poznata u znanosti. The suspensions of the present invention may preferably be obtained by either pressure filling or low temperature filling, both of which are well known in the art.
Suspenzije se mogu pokazati kao naročito poželjne za korištenje u inhalatorima za davanje odmjerene doze, jer zadovoljavaju uvjete efikasnosti i stabilnosti. Suspensions can prove to be particularly desirable for use in metered dose inhalers, as they meet the conditions of efficiency and stability.
Stručnjaci se mogu odlučiti i na dodavanje jednog ili više sredstava kao što su konzervansi, puferi, antioksidansi, zaslađivači i/ili aromatična sredstva i druga sredstva za maskiranje ukusa, u ovisnosti o karakteristikama konkretne formulacije. Experts may decide to add one or more agents such as preservatives, buffers, antioxidants, sweeteners and/or flavoring agents and other agents for masking the taste, depending on the characteristics of the specific formulation.
Primjeri I - XXXII opisuju primjere formulacija prema sadašnjem izumu, pri čemu su u nekima od njih dane i alternativne formulacije, označene kao "A" i "B". Examples I - XXXII describe examples of formulations according to the present invention, whereby in some of them alternative formulations are also given, designated as "A" and "B".
Primjer I Examples
[image] [image]
Primjer II Example II
[image] [image]
Primjer III Example III
[image] [image]
Primjer IV Example IV
[image] [image]
Primjer V Example V
[image] [image]
Primjer VI Example VI
[image] [image]
Primjer VII Example VII
[image] [image]
Primjer VIII Example VIII
[image] [image]
Primjer IX Example IX
[image] [image]
Primjer X Example X
[image] [image]
Primjer XI Example XI
[image] [image]
Primjer XII Example XII
[image] [image]
Primjer XIII Example XIII
[image] [image]
Primjer XIV Example XIV
[image] [image]
Primjer XV Example XV
[image] [image]
Primjer XVI Example XVI
[image] [image]
Primjer XVII Example XVII
[image] [image]
Primjer XVIII Example XVIII
[image] [image]
Primjer XIX Example XIX
[image] [image]
Primjer XX Example XX
[image] [image]
Primjer XXI Example XXI
[image] [image]
Primjer XXII Example XXII
[image] [image]
Primjer XXIII Example XXIII
[image] [image]
Primjer XXIV Example XXIV
[image] [image]
Primjer XXV Example XXV
[image] [image]
Primjer XXVI Example XXVI
[image] [image]
Primjer XXVII Example XXVII
[image] [image]
Primjer XXVIII Example XXVIII
[image] [image]
Primjer XXIX Example XXIX
[image] [image]
Primjer XXX Example XXX
[image] [image]
Primjer XXXI Example XXXI
[image] [image]
Primjer XXXII Example XXXII
[image] [image]
Iako su se primjeri odnosili na albuterol, albuterol sulfat, mometasone furoat, beklometazon dipropionat i klatrate beklometazon dipropionata, mogu se koristiti i drugi lijekovi predviđeni za oralno ili nazalno davanje. Slično, moguće je i korištenje ekscipijenata i površinski aktivnih sredstava koja nisu dana u primjerima. Although examples have been given of albuterol, albuterol sulfate, mometasone furoate, beclomethasone dipropionate, and beclomethasone dipropionate clathrate, other drugs intended for oral or nasal administration may be used. Similarly, it is also possible to use excipients and surfactants that are not given in the examples.
Opis navedenih realizacija izuma dan je samo kao ilustracija. Njegova namjena nije da iscrpi ili ograniči izum samo na konkretno dane oblike, jer je očigledno da se u okviru opisa mogu izvršiti mnoge modifikacije i varijacije. Realizacije su izabrane za opis tako da se na najbolji način objasne načela izuma i njegova praktična primjena, čime se drugim stručnjacima omogućava da izum koriste u različitim realizacijama i s različitim modifikacijama koje će ga prilagoditi konkretnoj namjeni. Obujam sadašnjeg izuma je definiran u priloženim patentnim zahtjevima. The description of the mentioned embodiments of the invention is given only as an illustration. It is not intended to exhaust or limit the invention only to the specifically given forms, as it is obvious that many modifications and variations can be made within the scope of the description. The realizations have been chosen for description so as to explain the principles of the invention and its practical application in the best way, thus enabling other experts to use the invention in different realizations and with different modifications that will adapt it to the specific purpose. The scope of the present invention is defined in the appended patent claims.
Claims (16)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HRP920362 HRP920362A2 (en) | 1992-09-21 | 1992-09-21 | Non-chlorofluorocarbon aerosol formulations |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HRP920362 HRP920362A2 (en) | 1992-09-21 | 1992-09-21 | Non-chlorofluorocarbon aerosol formulations |
Publications (1)
Publication Number | Publication Date |
---|---|
HRP920362A2 true HRP920362A2 (en) | 1995-08-31 |
Family
ID=10945760
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
HRP920362 HRP920362A2 (en) | 1992-09-21 | 1992-09-21 | Non-chlorofluorocarbon aerosol formulations |
Country Status (1)
Country | Link |
---|---|
HR (1) | HRP920362A2 (en) |
-
1992
- 1992-09-21 HR HRP920362 patent/HRP920362A2/en not_active Application Discontinuation
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6416743B1 (en) | Aerosol formulations of albuterol and 1,1,1,2-tetrafluoroethane | |
CA2111002C (en) | Non-chlorofluorocarbon aerosol formulations | |
IE83747B1 (en) | Non-chlorofluorocarbon aerosol formulations | |
KR100546239B1 (en) | pharmaceutical aerosol composition | |
US20010031244A1 (en) | Pharmaceutical aerosol composition | |
EP0789557A1 (en) | Propellant mixture for aerosol formulation | |
HRP920362A2 (en) | Non-chlorofluorocarbon aerosol formulations | |
HRP920381A2 (en) | Non-chlorofluorocarbon aerosol formulations | |
SI9400223A (en) | Non-chlorofluorocarbon aerosol formulations | |
SI9400222A (en) | Non-chlorofluorocarbon aerosol formulations |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A1OB | Publication of a patent application | ||
AIPI | Request for the grant of a patent on the basis of a substantive examination of a patent application | ||
ODBC | Application rejected |