EP1549288A1 - Nasal applizierbare pharmazeutische zubereitung und deren herstellung - Google Patents
Nasal applizierbare pharmazeutische zubereitung und deren herstellungInfo
- Publication number
- EP1549288A1 EP1549288A1 EP03747695A EP03747695A EP1549288A1 EP 1549288 A1 EP1549288 A1 EP 1549288A1 EP 03747695 A EP03747695 A EP 03747695A EP 03747695 A EP03747695 A EP 03747695A EP 1549288 A1 EP1549288 A1 EP 1549288A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- buffer
- preparation
- malic acid
- pharmaceutical preparation
- agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000000825 pharmaceutical preparation Substances 0.000 title claims abstract description 36
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 7
- 239000000872 buffer Substances 0.000 claims abstract description 47
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims abstract description 40
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims abstract description 39
- 239000001630 malic acid Substances 0.000 claims abstract description 39
- 235000011090 malic acid Nutrition 0.000 claims abstract description 39
- 239000003755 preservative agent Substances 0.000 claims abstract description 26
- 229960000686 benzalkonium chloride Drugs 0.000 claims abstract description 25
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000004480 active ingredient Substances 0.000 claims abstract description 23
- 238000002360 preparation method Methods 0.000 claims abstract description 23
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract description 18
- 239000000839 emulsion Substances 0.000 claims abstract description 11
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 10
- 239000000080 wetting agent Substances 0.000 claims abstract description 10
- 239000000203 mixture Substances 0.000 claims abstract description 8
- 239000002357 osmotic agent Substances 0.000 claims abstract description 8
- 239000010452 phosphate Substances 0.000 claims abstract description 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims abstract description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 5
- 239000000243 solution Substances 0.000 claims description 29
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 21
- 230000002335 preservative effect Effects 0.000 claims description 18
- 210000004081 cilia Anatomy 0.000 claims description 17
- 239000011780 sodium chloride Substances 0.000 claims description 11
- HUCJFAOMUPXHDK-UHFFFAOYSA-N Xylometazoline Chemical compound CC1=CC(C(C)(C)C)=CC(C)=C1CC1=NCCN1 HUCJFAOMUPXHDK-UHFFFAOYSA-N 0.000 claims description 8
- WYWIFABBXFUGLM-UHFFFAOYSA-N oxymetazoline Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C)=C1CC1=NCCN1 WYWIFABBXFUGLM-UHFFFAOYSA-N 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 108010000437 Deamino Arginine Vasopressin Proteins 0.000 claims description 6
- 230000003204 osmotic effect Effects 0.000 claims description 6
- 206010020751 Hypersensitivity Diseases 0.000 claims description 5
- 208000026935 allergic disease Diseases 0.000 claims description 5
- 230000007815 allergy Effects 0.000 claims description 5
- 229960004281 desmopressin Drugs 0.000 claims description 5
- NFLWUMRGJYTJIN-NXBWRCJVSA-N desmopressin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSCCC(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(N)=O)=O)CCC(=O)N)C1=CC=CC=C1 NFLWUMRGJYTJIN-NXBWRCJVSA-N 0.000 claims description 5
- PZJFUNZDCRKXPZ-UHFFFAOYSA-N 2,5-dihydro-1h-tetrazole Chemical compound C1NNN=N1 PZJFUNZDCRKXPZ-UHFFFAOYSA-N 0.000 claims description 4
- 102000055006 Calcitonin Human genes 0.000 claims description 4
- 108060001064 Calcitonin Proteins 0.000 claims description 4
- 239000000150 Sympathomimetic Substances 0.000 claims description 4
- 229960004015 calcitonin Drugs 0.000 claims description 4
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 claims description 4
- 229960000265 cromoglicic acid Drugs 0.000 claims description 4
- 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 claims description 4
- 150000002500 ions Chemical class 0.000 claims description 4
- 229960001528 oxymetazoline Drugs 0.000 claims description 4
- 230000001975 sympathomimetic effect Effects 0.000 claims description 4
- 229960000833 xylometazoline Drugs 0.000 claims description 4
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 3
- CNIIGCLFLJGOGP-UHFFFAOYSA-N 2-(1-naphthalenylmethyl)-4,5-dihydro-1H-imidazole Chemical compound C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 CNIIGCLFLJGOGP-UHFFFAOYSA-N 0.000 claims 6
- MBUVEWMHONZEQD-UHFFFAOYSA-N Azeptin Chemical compound C1CN(C)CCCC1N1C(=O)C2=CC=CC=C2C(CC=2C=CC(Cl)=CC=2)=N1 MBUVEWMHONZEQD-UHFFFAOYSA-N 0.000 claims 3
- 108010037003 Buserelin Proteins 0.000 claims 3
- 102400000932 Gonadoliberin-1 Human genes 0.000 claims 3
- 101500026183 Homo sapiens Gonadoliberin-1 Proteins 0.000 claims 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 3
- 108010021717 Nafarelin Proteins 0.000 claims 3
- 102400000050 Oxytocin Human genes 0.000 claims 3
- XNOPRXBHLZRZKH-UHFFFAOYSA-N Oxytocin Natural products N1C(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CC(C)C)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(O)C=C1 XNOPRXBHLZRZKH-UHFFFAOYSA-N 0.000 claims 3
- 101800000989 Oxytocin Proteins 0.000 claims 3
- 239000003470 adrenal cortex hormone Substances 0.000 claims 3
- 229960004574 azelastine Drugs 0.000 claims 3
- 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 claims 3
- 229960002719 buserelin Drugs 0.000 claims 3
- CUWODFFVMXJOKD-UVLQAERKSA-N buserelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 claims 3
- RKHQGWMMUURILY-UHRZLXHJSA-N cortivazol Chemical compound C([C@H]1[C@@H]2C[C@H]([C@]([C@@]2(C)C[C@H](O)[C@@H]1[C@@]1(C)C2)(O)C(=O)COC(C)=O)C)=C(C)C1=CC1=C2C=NN1C1=CC=CC=C1 RKHQGWMMUURILY-UHRZLXHJSA-N 0.000 claims 3
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 claims 3
- 229960001442 gonadorelin Drugs 0.000 claims 3
- 229940088597 hormone Drugs 0.000 claims 3
- 239000005556 hormone Substances 0.000 claims 3
- 229960004861 indanazoline Drugs 0.000 claims 3
- KUCWWEPJRBANHL-UHFFFAOYSA-N indanazoline Chemical compound C=12CCCC2=CC=CC=1NC1=NCCN1 KUCWWEPJRBANHL-UHFFFAOYSA-N 0.000 claims 3
- 229960001120 levocabastine Drugs 0.000 claims 3
- ZCGOMHNNNFPNMX-KYTRFIICSA-N levocabastine Chemical compound C1([C@@]2(C(O)=O)CCN(C[C@H]2C)[C@@H]2CC[C@@](CC2)(C#N)C=2C=CC(F)=CC=2)=CC=CC=C1 ZCGOMHNNNFPNMX-KYTRFIICSA-N 0.000 claims 3
- RWHUEXWOYVBUCI-ITQXDASVSA-N nafarelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 RWHUEXWOYVBUCI-ITQXDASVSA-N 0.000 claims 3
- 229960002333 nafarelin Drugs 0.000 claims 3
- 229960005016 naphazoline Drugs 0.000 claims 3
- 229960001723 oxytocin Drugs 0.000 claims 3
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 claims 3
- 229960001802 phenylephrine Drugs 0.000 claims 3
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 claims 3
- 108090000765 processed proteins & peptides Proteins 0.000 claims 3
- 229910052708 sodium Inorganic materials 0.000 claims 3
- 239000011734 sodium Substances 0.000 claims 3
- 229960001262 tramazoline Drugs 0.000 claims 3
- QQJLHRRUATVHED-UHFFFAOYSA-N tramazoline Chemical compound N1CCN=C1NC1=CC=CC2=C1CCCC2 QQJLHRRUATVHED-UHFFFAOYSA-N 0.000 claims 3
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 claims 3
- 229960005294 triamcinolone Drugs 0.000 claims 3
- 229960004495 beclometasone Drugs 0.000 claims 2
- 229940092705 beclomethasone Drugs 0.000 claims 1
- 238000004321 preservation Methods 0.000 claims 1
- 230000001886 ciliary effect Effects 0.000 abstract description 5
- 239000007864 aqueous solution Substances 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 230000000694 effects Effects 0.000 description 11
- 239000007922 nasal spray Substances 0.000 description 11
- 239000007853 buffer solution Substances 0.000 description 7
- 229940097496 nasal spray Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 6
- 229940100662 nasal drops Drugs 0.000 description 6
- 239000013543 active substance Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000007923 nasal drop Substances 0.000 description 5
- 210000001331 nose Anatomy 0.000 description 5
- 230000035559 beat frequency Effects 0.000 description 4
- 210000002850 nasal mucosa Anatomy 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000007979 citrate buffer Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- YGWFCQYETHJKNX-UHFFFAOYSA-N 2-[(4-tert-butyl-2,6-dimethylphenyl)methyl]-4,5-dihydro-1h-imidazol-3-ium;chloride Chemical compound [Cl-].CC1=CC(C(C)(C)C)=CC(C)=C1CC1=NCC[NH2+]1 YGWFCQYETHJKNX-UHFFFAOYSA-N 0.000 description 2
- 208000036071 Rhinorrhea Diseases 0.000 description 2
- 206010039101 Rhinorrhoea Diseases 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 210000000981 epithelium Anatomy 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229960003733 phenylephrine hydrochloride Drugs 0.000 description 2
- OCYSGIYOVXAGKQ-FVGYRXGTSA-N phenylephrine hydrochloride Chemical compound [H+].[Cl-].CNC[C@H](O)C1=CC=CC(O)=C1 OCYSGIYOVXAGKQ-FVGYRXGTSA-N 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000012088 reference solution Substances 0.000 description 2
- 230000008929 regeneration Effects 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 229960001095 xylometazoline hydrochloride Drugs 0.000 description 2
- IHOWSFVYYZTGSY-FOIRCHMTSA-N (2s)-2-amino-5-(diaminomethylideneamino)pentanoic acid;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N.OC(=O)[C@@H](N)CCCN=C(N)N.OC(=O)[C@@H](N)CCCN=C(N)N.OC(=O)CC(O)(C(O)=O)CC(O)=O IHOWSFVYYZTGSY-FOIRCHMTSA-N 0.000 description 1
- FIEYHAAMDAPVCH-UHFFFAOYSA-N 2-methyl-1h-quinazolin-4-one Chemical compound C1=CC=C2NC(C)=NC(=O)C2=C1 FIEYHAAMDAPVCH-UHFFFAOYSA-N 0.000 description 1
- 241000972773 Aulopiformes Species 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 102100026383 Vasopressin-neurophysin 2-copeptin Human genes 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 231100000481 chemical toxicant Toxicity 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- 229960002845 desmopressin acetate Drugs 0.000 description 1
- 201000010064 diabetes insipidus Diseases 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- KDQPSPMLNJTZAL-UHFFFAOYSA-L disodium hydrogenphosphate dihydrate Chemical compound O.O.[Na+].[Na+].OP([O-])([O-])=O KDQPSPMLNJTZAL-UHFFFAOYSA-L 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 208000031169 hemorrhagic disease Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000002262 irrigation Effects 0.000 description 1
- 238000003973 irrigation Methods 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 108010091858 peptide Q Proteins 0.000 description 1
- CCTIOCVIZPCTGO-BYPYZUCNSA-N phosphoarginine Chemical compound OC(=O)[C@@H](N)CCCNC(=N)NP(O)(O)=O CCTIOCVIZPCTGO-BYPYZUCNSA-N 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000012144 step-by-step procedure Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 229940064707 sympathomimetics Drugs 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 238000009736 wetting Methods 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
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to liquid, preserved pharmaceutical preparations for the application of various active substances to or in or over the nose of a patient in the form of a solution, their preparation and the use of a special buffer system for and in the preparations mentioned.
- nasal pharmaceutical preparations can either be used for the treatment or prevention of diseases on the nose itself or should lead to the absorption of active substances in the bloodstream so that they develop their effects elsewhere in the body.
- Medicines are primarily agents or active substances against runny nose, such as allergy agents, e.g. Cromoglicic acid, or sympathomimetics, e.g. Xylometazoline, tetrazoline,
- Oxymetazoline Naphazolin, Phenylephrin, to name.
- peptide Q preparations e.g. those with desmopressin as an active ingredient, which is an effective
- Nose drops contain at least one active ingredient
- Substances for setting a certain osmotic pressure e.g. NaCl
- / or 5 wetting or surface-active substances e.g. Cremophore
- auxiliaries for stabilizing the active ingredient or for maintaining a certain physiologically acceptable pH in the nose.
- phosphate or phosphate / citrate or citrate buffers and, under certain circumstances, acetate buffers are used. Furthermore, they contain in 0 most cases
- Benzalkonium chloride abbreviated BAC
- BAC Benzalkonium chloride
- benzalkonium chloride is widely used in mouth and throat disinfectants as well as wound and vaginal irrigation. Due to its good antimicrobial effectiveness and good tolerability, it is the most frequently used preservative that is used in nasal sprays and eye drops in conjunction with a large number of active pharmaceutical ingredients.
- the present invention thus relates to a new nasally applicable pharmaceutical preparation based on an aqueous, at least one per se known mucous membrane-absorbable and / or locally acting pharmaceutical active ingredient, at least one preservative formed by benzalkonium chloride alone or together with other preservatives, at least one buffer keeping the pH value at 4 to 6 or at about 5 and furthermore at least one osmotic and / or at least one wetting agent containing solution, emulsion or the like, which is characterized in that the preparation has a significantly improved compatibility with cilia in that in the same or in the underlying solution, emulsion or the like.
- the case per se in the field of pharmaceutical preparations is not so frequent that the essence of the same does not consist in a new active ingredient and its use in a pharmaceutical, but rather in the apparently much less spectacular area of a routine that has long since become routine
- Accompanying substance that has become established and has long proven itself in practice such as the buffer system contained in a pharmaceutical preparation and decisive for its effectiveness and durability, or in an unexpectedly positive change away from proven and widely used buffer systems for liquid pharmaceutical preparations to another buffer that is used much less frequently in medicinal products.
- composition ratios of the other components including the active ingredients in the various tried and tested pharmaceutical preparations can take place, while costly changes and administrative procedures can be saved.
- malic acid buffers in compositions for pharmaceutical and possibly also diagnostic purposes, reference is made, for example, to WO 98/47490 relating to the lyophilisates of biomolecules, in which, in addition to a larger number of different buffers based on organic acids, malic acid is also mentioned is, the buffers mentioned there serve to adjust the pH, but the main task of which is the formation of Use to prevent disruptive arginine-phosphate or citrate-protein aggregates that occur in known phosphate or citrate buffers.
- racemic is the simplest and quite effective embodiment Malic acid as a pH stabilizer and the ciliary-damaging effects are largely suppressing agents. However, enantiomerically pure malic acid can also be used instead of racemic malic acid.
- the A n s p r u c h 4 names NaCI as a particularly proven osmosis-active ingredient in connection with the cily-friendly effect of the new pharmaceutical preparations.
- Another essential object of the present invention is the method for producing the new nasally administrable pharmaceutical preparation, the details of which are given in claim 6, the essential ⁇ l Characteristic of this production process is the targeted replacement of the previously used - and in the course of the investigations of the present invention as - in the presence of benzalkonium chloride - buffer systems which prove to be very dangerous for the cilia activity by a malic acid buffer. 5
- claims 7 and 8 which are subordinate to production claim 6 and referenced to it, are analogous to the features of claims 2 to 6 already explained above.
- Another essential objective of the invention is to -As described above - surprisingly discovered and previously nowhere about only ⁇ ⁇ suggestively mentioned use of based on malic acid as an essential component buffer system instead of usual buffers for the preparation of cilienver juxtaposen, nasally administrable pharmaceutical preparations, the details are not cited here and are disclosed in claim 9. 5
- the beat frequency of the cilia is reduced significantly less by solution 1 with malic acid buffer than by solution 2 with the usual buffer. Then the self-cleaning of the nasal mucosa is simulated by washing out the respective solutions and adding Ringer's solution over 45 minutes. Afterwards, a clear recovery of the cilia beat frequency is achieved in solution 1 with the malic acid buffer, increased from 48 to 74%.
- Example 2 In a 5 liter beaker, 4900 g of aqua dest. submitted and in it
- Phenylephrine hydrochloride dissolved with stirring. The pH is adjusted to 5 with 1 N NaOH. It is made with aqua dest. made up to 5 l and the solution obtained becomes
- Nasal drops or processed into a nasal spray Nasal drops or processed into a nasal spray.
- the beat frequency of the cilia is reduced significantly less by the sample solutions with malic acid buffer than by the reference solutions. Then the self-cleaning of the nasal mucosa is simulated by washing out the test solutions and adding a Ringer's solution over 45 min.
- a significantly better recovery of the ciliac impact is achieved, which reaches up to over% of the initial impact (of 100%). This is a very good value, especially since even if the cilia are incubated in physiological saline after 45 min, only 55% of the cilia initial beat frequency is obtained.
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Otolaryngology (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Pulmonology (AREA)
- Neurosurgery (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT15402002 | 2002-10-10 | ||
| AT0154002A AT413078B (de) | 2002-10-10 | 2002-10-10 | Verwendung eines puffers auf basis von apfelsäure für die herstellung einer nasal applizierbaren zubereitung |
| PCT/AT2003/000306 WO2004032896A1 (de) | 2002-10-10 | 2003-10-09 | Nasal applizierbare pharmazeutische zubereitung und deren herstellung |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1549288A1 true EP1549288A1 (de) | 2005-07-06 |
Family
ID=32074994
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP03747695A Withdrawn EP1549288A1 (de) | 2002-10-10 | 2003-10-09 | Nasal applizierbare pharmazeutische zubereitung und deren herstellung |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US20060127317A1 (enExample) |
| EP (1) | EP1549288A1 (enExample) |
| JP (1) | JP2006503868A (enExample) |
| AT (1) | AT413078B (enExample) |
| AU (1) | AU2003266811A1 (enExample) |
| CA (1) | CA2501760A1 (enExample) |
| NO (1) | NO20052251L (enExample) |
| PL (1) | PL375762A1 (enExample) |
| WO (1) | WO2004032896A1 (enExample) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102007006122A1 (de) * | 2007-02-02 | 2008-08-07 | Krewel Meuselbach Gmbh | Cistusextrakte |
| US20130213393A1 (en) | 2009-12-22 | 2013-08-22 | Evoke Pharma, Inc. | Nasal formulations of metoclopramide |
| WO2015054429A1 (en) * | 2013-10-08 | 2015-04-16 | Innopharma, Inc | Aprepitant oral liquid formulations |
| US11517545B2 (en) | 2016-12-15 | 2022-12-06 | Evoke Pharma, Inc. | Treatment of moderate and severe gastroparesis |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5514670A (en) * | 1993-08-13 | 1996-05-07 | Pharmos Corporation | Submicron emulsions for delivery of peptides |
| AT409081B (de) * | 2000-02-16 | 2002-05-27 | Gebro Pharma Gmbh | Stabile, nasal, oral oder sublingual anwendbare pharmazeutische zubereitung |
-
2002
- 2002-10-10 AT AT0154002A patent/AT413078B/de active
-
2003
- 2003-10-09 US US10/530,969 patent/US20060127317A1/en not_active Abandoned
- 2003-10-09 EP EP03747695A patent/EP1549288A1/de not_active Withdrawn
- 2003-10-09 WO PCT/AT2003/000306 patent/WO2004032896A1/de not_active Ceased
- 2003-10-09 PL PL03375762A patent/PL375762A1/xx not_active Application Discontinuation
- 2003-10-09 AU AU2003266811A patent/AU2003266811A1/en not_active Abandoned
- 2003-10-09 JP JP2004542079A patent/JP2006503868A/ja not_active Withdrawn
- 2003-10-09 CA CA002501760A patent/CA2501760A1/en not_active Abandoned
-
2005
- 2005-05-09 NO NO20052251A patent/NO20052251L/no not_active Application Discontinuation
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2004032896A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2004032896A1 (de) | 2004-04-22 |
| NO20052251L (no) | 2005-05-09 |
| PL375762A1 (en) | 2005-12-12 |
| US20060127317A1 (en) | 2006-06-15 |
| AT413078B (de) | 2005-11-15 |
| ATA15402002A (de) | 2005-04-15 |
| AU2003266811A1 (en) | 2004-05-04 |
| JP2006503868A (ja) | 2006-02-02 |
| CA2501760A1 (en) | 2004-04-22 |
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