ZA200007581B - Pharmaceutical formulations for aerosols with two or more active substances. - Google Patents
Pharmaceutical formulations for aerosols with two or more active substances. Download PDFInfo
- Publication number
- ZA200007581B ZA200007581B ZA200007581A ZA200007581A ZA200007581B ZA 200007581 B ZA200007581 B ZA 200007581B ZA 200007581 A ZA200007581 A ZA 200007581A ZA 200007581 A ZA200007581 A ZA 200007581A ZA 200007581 B ZA200007581 B ZA 200007581B
- Authority
- ZA
- South Africa
- Prior art keywords
- preparation according
- pharmaceutical preparation
- acid
- active substances
- propellant
- Prior art date
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- 239000013543 active substance Substances 0.000 title claims description 38
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 4
- 239000000443 aerosol Substances 0.000 title description 7
- 239000000203 mixture Substances 0.000 claims description 19
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 19
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- 238000009472 formulation Methods 0.000 claims description 17
- 239000003381 stabilizer Substances 0.000 claims description 15
- 239000004094 surface-active agent Substances 0.000 claims description 15
- 239000003380 propellant Substances 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 239000000725 suspension Substances 0.000 claims description 13
- 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 9
- 239000002253 acid Substances 0.000 claims description 8
- 229960002052 salbutamol Drugs 0.000 claims description 8
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical group FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 claims description 7
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 7
- 239000000194 fatty acid Substances 0.000 claims description 7
- 229930195729 fatty acid Natural products 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000006184 cosolvent Substances 0.000 claims description 6
- -1 fatty acid esters Chemical class 0.000 claims description 6
- 229960001361 ipratropium bromide Drugs 0.000 claims description 6
- 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 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 150000004665 fatty acids Chemical class 0.000 claims description 5
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 claims description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 3
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 3
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 3
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 claims description 3
- 239000005642 Oleic acid Substances 0.000 claims description 3
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 3
- 229960004436 budesonide Drugs 0.000 claims description 3
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 3
- RQTOOFIXOKYGAN-UHFFFAOYSA-N nedocromil Chemical compound CCN1C(C(O)=O)=CC(=O)C2=C1C(CCC)=C1OC(C(O)=O)=CC(=O)C1=C2 RQTOOFIXOKYGAN-UHFFFAOYSA-N 0.000 claims description 3
- 229960004398 nedocromil Drugs 0.000 claims description 3
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 3
- 229920000642 polymer Polymers 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
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 150000001298 alcohols Chemical group 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- 229960005070 ascorbic acid Drugs 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 2
- 150000001720 carbohydrates Chemical class 0.000 claims description 2
- 235000014633 carbohydrates Nutrition 0.000 claims description 2
- 150000002191 fatty alcohols Chemical class 0.000 claims description 2
- 125000005456 glyceride group Chemical group 0.000 claims description 2
- 239000000787 lecithin Substances 0.000 claims description 2
- 229940067606 lecithin Drugs 0.000 claims description 2
- 235000010445 lecithin Nutrition 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 229920000136 polysorbate Polymers 0.000 claims description 2
- 229940068965 polysorbates Drugs 0.000 claims description 2
- 229960004017 salmeterol Drugs 0.000 claims description 2
- 229910021653 sulphate ion Inorganic materials 0.000 claims description 2
- 229960000195 terbutaline Drugs 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 101150087188 Mast1 gene Proteins 0.000 claims 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims 1
- 229960004106 citric acid Drugs 0.000 claims 1
- OEXHQOGQTVQTAT-JRNQLAHRSA-N ipratropium Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 OEXHQOGQTVQTAT-JRNQLAHRSA-N 0.000 claims 1
- 229960001888 ipratropium Drugs 0.000 claims 1
- 229940074355 nitric acid Drugs 0.000 claims 1
- 229960004838 phosphoric acid Drugs 0.000 claims 1
- 239000002245 particle Substances 0.000 description 16
- 239000000126 substance Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 5
- 230000008901 benefit Effects 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical class CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 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 description 3
- 239000004615 ingredient Substances 0.000 description 3
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- LSLYOANBFKQKPT-DIFFPNOSSA-N 5-[(1r)-1-hydroxy-2-[[(2r)-1-(4-hydroxyphenyl)propan-2-yl]amino]ethyl]benzene-1,3-diol Chemical compound C([C@@H](C)NC[C@H](O)C=1C=C(O)C=C(O)C=1)C1=CC=C(O)C=C1 LSLYOANBFKQKPT-DIFFPNOSSA-N 0.000 description 2
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- 229960001171 acetohydroxamic acid Drugs 0.000 description 2
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone 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)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229960001022 fenoterol Drugs 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- LMOINURANNBYCM-UHFFFAOYSA-N metaproterenol Chemical compound CC(C)NCC(O)C1=CC(O)=CC(O)=C1 LMOINURANNBYCM-UHFFFAOYSA-N 0.000 description 2
- 229960002657 orciprenaline Drugs 0.000 description 2
- 229960001609 oxitropium bromide Drugs 0.000 description 2
- LCELQERNWLBPSY-KHSTUMNDSA-M oxitropium bromide Chemical compound [Br-].C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3[N+]([C@H](C2)[C@@H]2[C@H]3O2)(C)CC)=CC=CC=C1 LCELQERNWLBPSY-KHSTUMNDSA-M 0.000 description 2
- 229960002720 reproterol Drugs 0.000 description 2
- WVLAAKXASPCBGT-UHFFFAOYSA-N reproterol Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2N=CN1CCCNCC(O)C1=CC(O)=CC(O)=C1 WVLAAKXASPCBGT-UHFFFAOYSA-N 0.000 description 2
- 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 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- AWRLZJJDHWCYKN-UHFFFAOYSA-N 5-bromo-2-ethoxy-3-nitropyridine Chemical compound CCOC1=NC=C(Br)C=C1[N+]([O-])=O AWRLZJJDHWCYKN-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 229960004495 beclometasone Drugs 0.000 description 1
- 229940092705 beclomethasone Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- IMZMKUWMOSJXDT-UHFFFAOYSA-N cromoglycic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C(O)=O)O2 IMZMKUWMOSJXDT-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000012899 de-mixing Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940071106 ethylenediaminetetraacetate Drugs 0.000 description 1
- 229960001037 fenoterol hydrobromide Drugs 0.000 description 1
- 238000005189 flocculation Methods 0.000 description 1
- 230000016615 flocculation Effects 0.000 description 1
- 229960000676 flunisolide Drugs 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229960002714 fluticasone Drugs 0.000 description 1
- MGNNYOODZCAHBA-GQKYHHCASA-N fluticasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001282 iso-butane Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- 210000003800 pharynx Anatomy 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- MIXMJCQRHVAJIO-TZHJZOAOSA-N qk4dys664x Chemical compound O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O MIXMJCQRHVAJIO-TZHJZOAOSA-N 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 231100000583 toxicological profile Toxicity 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—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]
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- 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
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Emergency Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Otolaryngology (AREA)
- Pulmonology (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
« ‘ a. ’
Cr WO 99/65464 PCT/US99/12785
Prosecution application
Pharmaceutical Formulations for Aerosols with two or more
Active Substances SE
The present invention relates to new pharmaceutical formulations for aerosols with at least two or more active substances for use by inhalation or by the nasal route.
State of the art
In propellant-driven metered dose inhalers (MDI) the active substances can be formulated as solutions or suspensions. The vast majority of aerosol formulations for MDI's are prepared as suspensions, especially if the preparation contains more than one active substance.
Formulations in the form of solutions are used only to a limited extent. In these cases, the formulations normally contain only one active substance.
As a rule, in a suspension, the chemical stability of the active substances is noticeably higher than in a solution. o 25 Additionally, in a suspension the active substance can be more highly concentrated than in a solution, with the “4 result that suspension type formulation enable higher doses to be administered.
A major disadvantage of suspension-formulations is the fact that over time (e.g. during storage) the suspended particles clump together to form bigger, more or less stable agglomerates or form loose flakes, sediments or floating layers, or in the worst case, particle growth, ~ 35 which significantly impairs the pharmaceutical quality of the product. The size of the particles formed or the py - , speed of particle growth are influenced by the solubilitwv features of the liguid phase. Thus, ingress of humidity during storage or a desired increase in polarity, e.q. achieved by adding co-solvents, can have a devastating effect on the quality of the medical end product, particularly if the suspended particles have polar } structure elements. The suspension can be physically stabilised by the addition of surfactants, by reducing the harmful effects of moisture and/or particle growth so that suspended particles can be held in suspension for longer.
Natural solution-type formulations are not affected by the problems of increasing particle size or de-mixing processes such as sedimentation or flocculation. However, in this case there is a serious risk of chemical degradation. A further disadvantage is the fact that the limited solubility of the ingredients can prevent administration in high doses. In the past, the chlorofluorchydrocarbons TG 11 ({trichlorofluoroumethiane),
TG 12 (dichlorodifluoromethane) and TG 114 (dichlorotetrafluoroethane) have proved particularly suitable as solvents. The solubility of the ingredients can be increased by the addition of co-solvents. In addition, it is usually necessary to take additional measures to chemically stabilise the dissolved components. *
Up till now, CFCs such as the above-mentioned TG 11, for ? example, have often been used as propellants. However, since CFCs have been linked with the destruction of the ozone layer, their manufacture and use are being phased out. The intention is to replace them with special fluorohydrocarbons (HFC) which are less destructive to the ozone layer but have completely different solubility features. The toxicological profile and physico-chemical . 35 properties such as the steam pressure, for example, determine which HFCs are suitable for MDIs. The most
. a ten promising representatives at present are TG 134a (1,1,2,2- © tetrafluoroethane) and TG 227 (1,1,1,2,3,3,3- heptafluoropropane) .
For inhalative treatment it may be desirable to have aerosol formulations with two or more active substances.
In such cases the active substances are formulated in the necessary concentrations as solutions or suspensions, frequently giving rise to problems regarding the chemical stability of the individual substances or the degree of concentration which can be attained. Major problems are encountered if one of the active substances cannot be suspended or is unstable in a suspension-type formulation of this kind or if one of the active substances is chemically unstable or will not dissolve in a solution- : type formulation of this kind, particularly when HFC is : used as the propellant. > It is therefore one object of the present invention to : 20 develop a formulation for metering aerosols having two or more active substances which overcomes the above-mentioned disadvantages.
Description of the invention * 25 : :
Surprisingly, it has been found that a plurality of active “ substances can be formulated as a solution and a . suspension combined in one formulation.
The invention relates to stable aerosol formulations with fluorohydrocarbons as propellants, particularly TG 134a and/or TG 227, consisting of two or more active substances, wherein at least one active substance is : formulated as a solution and at least one active substance . 35 is formulated as a suspension. The pharmaceutical preparation according to the invention is used for inhalative treatment, particularly for treating diseases of the pharynx and respiratory tract, e.g. asthmatic cliseases and COPD.
In one embodiment a medicinally useful combination of two or more active substances is used, containing beclometasone, budesonide, cromoglycinic acid, fenoterol, flunisolide, fluticasone, ipratropium bromide, nedocromil, orciprenaline, oxitropium bromide, reproterol, salbutamol (albuterol), salmeterol, terbutalin, N-[[2,2-dimethyl-4- (2-oxo-2H-pyridin-1-yl)-6-trifluoromethyl-2H-1-benzopyran- 3-yllmethyl] -N-hydroxy-acetamide, the esters, salts and/or solvates thereof. Which of the above-mentioned active substances is formulated as a solution and which as a suspension in the preparation according to the invention depends on the particular combinations of active substance and can be determined relatively quickly by solution and suspension trials.
In a preferred embodiment, one or more of the following active substances are suspended: budesonide, cromoglycinic acid, nedocromil, reproterol and/or salbutamol (albuterol) or the esters, salts and/or solvates derived from these ’ compounds and one or more of the following substances are dissolved: beclomethasone, fenoterol, ipratropium bromide, ’ orciprenaline and/or oxitropium bromide, N-[[2,2-dimethyl- 4- (2-0x0-2H-pyridin-1-yl)-6-trifluoromethyl-2H-1-
Dbenzopyran-3-yllmethyl] -N-hydroxy-acetamide or the esters, salts and/or solvates derived from these compounds.
Embodiments having two different active substances are preferred. . 35 A particularly preferred embodiment contains dissolved ipratropium bromide, particularly combined with salbutamol
¢ - Fu, sulphate (albuterol sulphate) as the suspended active © substance.
In all the embodiments, the active substances are used in a therapeutically effective quantity, i.e. in a quantity that can induce a successful treatment. The concentration of the active substances and the volume per stroke of - spray are adjusted in such a way that the quantity of active substance which is medically necessary or recommended is released by a single spray or by a few sprays. oo
One embodiment relates to formulations in which the suspended particles are stabilised by the addition of 5 15 surfactant substances (surfactants) or other suspension- ai stabilising agents to stabilise the suspended particles 5, against physical changes. The benefit of this is that the 0 particle size will remain pharmaceutically acceptable even 5 over lengthy periods, e.g. during storage. Preferred particle sizes are up to 20 pum, whilst particularly preferred particle sizes are between 5 and 15 pm, best of all not exceeding 10 pm. The advantage of these particle sizes is that the particles are small enough to penetrate deeply into the lungs but not so small as to be breathed
A 25 out again with the exchanged air. ¥ Suitable surfactants and suspension-stabilising agents include all pharmacologically acceptable substances which have a lipophilic hydrocarbon group and one or more functional hydrophilic groups, especially C.,, fatty alcohols, C..,, fatty acids, C.,, fatty acid esters, lecithin, glycerides, propyleneglycol esters, polyoxyethylenes, polysorbates, sorbitan esters and/or carbohydrates. Ceo fatty acids, propyleneglycol diesters . 35 and/or triglycerides and/or sorbitans of the C.,, fatty acids are preferred, whilst oleic acid and sorbitan mono-,
" . , di- or triocleates are particularly preferred.
Alternatively. toxicologically and pharmaceutically acceptable polymers and block-polymers can be used as suspension-stabilising agents. The surfactants used are either non-fluorinated or partially fluorinated or perflucrinated, the term flucrinatcd referring Lo Lhe exchange of hydrogen radicals bound to the carbon for fluorine radicals. The quantity of surfactant may be up to 1:1 based on the proportion by weight of the suspended active substances; amounts of 0.0001:1 to 0.5:1 are preferred, whilst amounts of from 0.0001:1 to 0.25:1 are particularly preferred.
A further advantage of the above surfactants is that they can also be used as valve lubricants. Therefore, one embodiment relates to formulations in which said surfactants are added as valve lubricants.
In another embodiment the solubility of at least one active substance to be dissolved is increased by the addition of one or more co-solvents. This has the advantage that the active substance or substances to be dissolved can be formulated in higher concentrations. The addition of co-solvent must not exceed the critical threshold of polarity of the liquid phase at which one of g the disadvantages described above begins to affect the suspended particles of active substance. ‘
Suitable co-solvents are pharmacologically acceptable alcohols such as ethanol, esters or water or mixtures thereof; ethanol is preferred. The concentration of the co-solvent in relation to the total formulation may be from 0.0001 to 50 wt.-%, preferably 0.0001 to 25 wt.-%.
In another embodiment a concentration of 0.0001 to 10 wt.-% is preferred whilst particularly preferred embodiments are those wherein just enough alcohol is added
. . . to dissolve the active substance which has to be © dissolved.
In another embodiment, other common propellants are added to the HFC propellant. These added propellants may be, beside other HFCs, saturated lower hydrocarbons such as propane, butane, isobutane or pentane provided that the . mixture is pharmacologically acceptable.
In one embodiment, stabilisers are added to the formulation, with a beneficial effect on the pharmaceutical stability of the active substances even over lengthy periods, e.g. during storage. In the context of the invention, stabilisers denotes those substances . 15 which prolong the durability and usability of the an pharmaceutical preparation by preventing or delaying yo chemical changes in the individual ingredients, particularly the active substances, e.g. caused by
SE subsequent reactions or degradation, or those which vo 20 prevent biological contamination. Stabilisers which are
SE preferred for this purpose are those which influence the pH of the liquid phase, such as acids and/or the salts thereof, particularly suitable substances are hydrochloric ) acid, sulphuric acid, nitric acid, phosphoric acid, * 25 . ascorbic acid, citric acid and the salts thereof. In addition, preferred bactericides, fungicides etc. are k benzalkonium chloride or ethylene diamine tetraacetate.
Citric acid is most preferred. The concentration of the stabilisers may be up to 1000 ppm, preferably up to 100 ppm and most preferably 20 to 40 ppm.
One particularly preferred embodiment comprises suspended salbutamol sulphate (albuterol sulphate), dissolved ipratropium bromide, ethanol as co-solvent and citric acid . 35 as stabiliser.
Example 1 ln a solution of liquefied 8Y.Y6 g (L mol, 89.71 wt.-%) of
TG 134a and 10.03 g (218 mmol, 10.00% hy weiaht) of ethanol are dissolved 37 mg (0.09 mmol, 0.037 wt.-%) of ipratropium bromide and 4 mg (20 pmol, 0.004% by weight) of citric acid and 210.5 mg (0.88 mmol, 0.21% by weight) of salbutamol sulphate (albuterol sulphate) are suspended together with 0.05% by weight of surfactant (e.g. 50 mg (177 mmol) of oleic acid).
Example 2
Analogous to Example 1 using TG 227 as the propellant gas instead of TG 134a.
Example 3
Disodium chromoglycate is suspended in liquefied P134 and a small amount of ethanol and fenoterol hydrobromide is dissolved therein.
Example 4 »
Analogous to Example 3 using TG 227 as propellant gas { instead of TG 134a.
Claims (21)
1. Pharmaceutical preparation for propellant driven meterad dese inhalers having a fluorohydrocarbon (HFC) as propellant, which cantains a combination of two or more active substances at |sast one of which is dissolved and at least one of which is suspended characterised in that the formulation comprises 2 co- solvent fo increase the solubility of the at |sast one active substance that is dissolved, whereas the co-solvent is selected from alcohols, a pharmacologically tolerable ester, water or a mixfure thareaf, .
2. Pharmaceutical preparation according to claim 1, characterised in that the combination of active substances consists of two active substances.
3. Pharmaceutical preparation according to ons of the preceding claims, characterised in that the propellant is TG 134a and/or TG 227,
4. Pharmaceutcal preparation according to claim 3, characterised in that the co- solvent is ethanol. :
3. Pharmaceutical preparation accarding to claim 3 or 4, characterised in that the co-solvant is present in a concentration of up to 25% by weight, based on the quantity of liqusfied propellant. :
&. Pharmaceutical preparation according to claim 3, 4 or 5, characterised in that the co-sojvent is present in a concentration of up to 10% by weight, based on - the quantity of liquefied propellant. :
7. ~harmaceutical preparation according to claim 1, 2,3, 4, 5 or 8, characterisad ~inthat the compasition is stabilised by a stabiliser,
8. Pharmaceutical preparation according to claim 7, charactarisad in that the stabiliser contains one or mora acids and/or salts.
eg. Pharmacetiiical preparation according io claim 7 ar &, characistisad in £hat the stabiliser(s) contain(s) hydrochiaric acid, suiphuric acid, nitric acid, phosphoric acid, ascorbic acid, citric acid, benzalkonium chloride and/or sthylene d famine tatrzaceiic and/or g sali thereof, AMENDED SHEET i
10. Pharmaceutical preparation according to claim 7 to 9, characterised in that the stahiliser is citric acid,
tM. Pharmaceutical preparation according to one of the preceding claims 7 to 1G, characterised in that the stabiliser is present in an amount of up to 100 ppm.
12. Pharmaceutical preparation according to one of the preceding claims 7 to 10, characterised in that the stabiliser is present in an amount of up to 40 ppm. :
13. Pharmaceutical preparation according to one of the preceding claims 1 10 12, characterised in that the preparation contains a surfactant or suspension stabilising agent.
14. Pharmaceutical preparation according to claim 13, characterisad in that the surfactant contains Cs. fatty alcohols, Caen fatty acids, Cs.an fatty acid esters, lecithin, glycerides, propyieneglycol esters, polyoxyesthanes, polysorbates, sorbitan esters and/or carbohydrates. : oo © 45.
Pharmaceutical preparation according to claim 14, characterised in that the Co © surfactant contains Cz fatty acids and/or the esters thersof. -
16. Pharmaceutical preparation according fo claim 13, characterised in that the surfactant contains olsic acid and/or sorbitan mono-, di- or tricleate.
17. Pharmaceutical preparation according io claim 13, characterised in that the - surfactant contains oleic acid, :
18. Pharmaceutical composition according 1s claim 13 characterised in that the surfactant or suspension-stabilising agent comprisas a toxicologically : acceptable polymer and/or block-polymsr,
19. Pharmaceutical preparation according io one of the pracading claims, charactarisad in that the active substance combination caniains baclomethasona, budesonide, cromogivainic acid, fencterol, fiunisclide, fluticasang, ipratropium, nedocromil, orcipranaling, oxjtronium bromide. raproteral, salbutamol, salmeterol (albuterol), terbutalin, N-{[2,2-dimethyi-4~(2- oxo-2H-pyridin-1-yl)-8-triffuaromethyi-2--1-banzopyran-3-yiimathyl-N- nvdrapv-gostamids, the asiars, salts and/or solvatss thersal, a AMENDED SHEET
20. Pharmaceutical preparation according to one of claims 1 to 19, characterised in that the active substance combination contains salbutamol sulphate (albuterol : sulphate) and ipratropium bromide.
21. Pharmaceutical preparation according to any one of claims 1 to 20, substantially as herein described and exemplified. AMENDED SHEET A
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1998127178 DE19827178A1 (en) | 1998-06-18 | 1998-06-18 | Stable aerosol formulations containing two or more bioactives used for pharmaceuticals |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200007581B true ZA200007581B (en) | 2002-05-29 |
Family
ID=7871289
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200007581A ZA200007581B (en) | 1998-06-18 | 1999-06-08 | Pharmaceutical formulations for aerosols with two or more active substances. |
Country Status (3)
| Country | Link |
|---|---|
| DE (1) | DE19827178A1 (en) |
| UA (1) | UA73721C2 (en) |
| ZA (1) | ZA200007581B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10104367A1 (en) * | 2001-02-01 | 2002-08-08 | Boehringer Ingelheim Pharma | Medicinal compositions containing betamimetics with fewer side effects |
| DE10104370A1 (en) * | 2001-02-01 | 2002-08-08 | Boehringer Ingelheim Pharma | Medicinal compositions with fewer side effects |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8828477D0 (en) * | 1988-12-06 | 1989-01-05 | Riker Laboratories Inc | Medical aerosol formulations |
| US5589156A (en) * | 1994-05-02 | 1996-12-31 | Henry; Richard A. | Prilocaine and hydrofluourocarbon aerosol preparations |
| US5496537A (en) * | 1995-03-23 | 1996-03-05 | Henry; Richard A. | Propofol hydrofluorocarbon propellant formulations |
-
1998
- 1998-06-18 DE DE1998127178 patent/DE19827178A1/en not_active Withdrawn
-
1999
- 1999-06-08 ZA ZA200007581A patent/ZA200007581B/en unknown
- 1999-08-06 UA UA2001010409A patent/UA73721C2/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| UA73721C2 (en) | 2005-09-15 |
| DE19827178A1 (en) | 2000-04-27 |
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