WO2019154895A1 - Formulation en gel pour la prévention ou le traitement de la perte auditive - Google Patents
Formulation en gel pour la prévention ou le traitement de la perte auditive Download PDFInfo
- Publication number
- WO2019154895A1 WO2019154895A1 PCT/EP2019/052971 EP2019052971W WO2019154895A1 WO 2019154895 A1 WO2019154895 A1 WO 2019154895A1 EP 2019052971 W EP2019052971 W EP 2019052971W WO 2019154895 A1 WO2019154895 A1 WO 2019154895A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutical composition
- auris
- poloxamer
- gel
- ppar agonist
- Prior art date
Links
- 208000016354 hearing loss disease Diseases 0.000 title claims abstract description 80
- 206010011878 Deafness Diseases 0.000 title claims abstract description 77
- 230000010370 hearing loss Effects 0.000 title claims abstract description 77
- 231100000888 hearing loss Toxicity 0.000 title claims abstract description 77
- 230000003405 preventing effect Effects 0.000 title claims abstract description 45
- 239000000203 mixture Substances 0.000 title claims description 82
- 238000009472 formulation Methods 0.000 title description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 236
- 210000002768 hair cell Anatomy 0.000 claims abstract description 137
- 229940126033 PPAR agonist Drugs 0.000 claims abstract description 125
- 239000002307 peroxisome proliferator activated receptor agonist Substances 0.000 claims abstract description 125
- 230000007850 degeneration Effects 0.000 claims abstract description 42
- 230000030833 cell death Effects 0.000 claims abstract description 41
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 14
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 claims description 108
- 238000000034 method Methods 0.000 claims description 105
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 81
- 229920002125 Sokalan® Polymers 0.000 claims description 65
- 229920001983 poloxamer Polymers 0.000 claims description 61
- 239000000872 buffer Substances 0.000 claims description 59
- -1 polyoxyethylene Polymers 0.000 claims description 58
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 58
- 229920001577 copolymer Polymers 0.000 claims description 57
- 229960005095 pioglitazone Drugs 0.000 claims description 55
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 51
- 150000003839 salts Chemical class 0.000 claims description 48
- 229920000642 polymer Polymers 0.000 claims description 44
- 229960000502 poloxamer Drugs 0.000 claims description 41
- 230000002209 hydrophobic effect Effects 0.000 claims description 38
- 239000004094 surface-active agent Substances 0.000 claims description 37
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 33
- 229920000136 polysorbate Polymers 0.000 claims description 32
- 229920001992 poloxamer 407 Polymers 0.000 claims description 31
- 229940044476 poloxamer 407 Drugs 0.000 claims description 28
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 27
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 27
- 150000001875 compounds Chemical class 0.000 claims description 27
- 239000003795 chemical substances by application Substances 0.000 claims description 24
- 229920000728 polyester Polymers 0.000 claims description 23
- 239000000344 soap Substances 0.000 claims description 23
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 22
- 229920002678 cellulose Polymers 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 22
- 229960004418 trolamine Drugs 0.000 claims description 22
- 230000003232 mucoadhesive effect Effects 0.000 claims description 21
- 239000003623 enhancer Substances 0.000 claims description 20
- 230000035699 permeability Effects 0.000 claims description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 19
- 239000001913 cellulose Substances 0.000 claims description 19
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 19
- 229920000053 polysorbate 80 Polymers 0.000 claims description 19
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 17
- 229920002472 Starch Polymers 0.000 claims description 15
- 229940068968 polysorbate 80 Drugs 0.000 claims description 15
- 239000003755 preservative agent Substances 0.000 claims description 15
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 14
- 229910052914 metal silicate Inorganic materials 0.000 claims description 14
- 239000008107 starch Substances 0.000 claims description 14
- 235000019698 starch Nutrition 0.000 claims description 14
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 13
- 229910052782 aluminium Inorganic materials 0.000 claims description 13
- 239000008119 colloidal silica Substances 0.000 claims description 13
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 12
- 229920001206 natural gum Polymers 0.000 claims description 12
- 229940068965 polysorbates Drugs 0.000 claims description 12
- 239000011701 zinc Substances 0.000 claims description 12
- 229910052725 zinc Inorganic materials 0.000 claims description 12
- 230000002335 preservative effect Effects 0.000 claims description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 10
- 239000003963 antioxidant agent Substances 0.000 claims description 10
- 229920001993 poloxamer 188 Polymers 0.000 claims description 10
- 229940057995 liquid paraffin Drugs 0.000 claims description 9
- 229940044519 poloxamer 188 Drugs 0.000 claims description 9
- 239000010685 fatty oil Substances 0.000 claims description 8
- 230000003078 antioxidant effect Effects 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 5
- 229910019142 PO4 Inorganic materials 0.000 claims description 5
- 235000019270 ammonium chloride Nutrition 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 5
- 239000010452 phosphate Substances 0.000 claims description 5
- 229920002511 Poloxamer 237 Polymers 0.000 claims description 4
- 229920002517 Poloxamer 338 Polymers 0.000 claims description 4
- 229920001451 polypropylene glycol Polymers 0.000 claims description 4
- 239000000499 gel Substances 0.000 description 179
- 239000000243 solution Substances 0.000 description 72
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 43
- 241001465754 Metazoa Species 0.000 description 39
- 229960001631 carbomer Drugs 0.000 description 39
- 208000014674 injury Diseases 0.000 description 33
- 230000008569 process Effects 0.000 description 33
- 230000008733 trauma Effects 0.000 description 31
- 238000011282 treatment Methods 0.000 description 31
- 239000000556 agonist Substances 0.000 description 30
- 239000002202 Polyethylene glycol Substances 0.000 description 26
- 210000003027 ear inner Anatomy 0.000 description 26
- 229920001223 polyethylene glycol Polymers 0.000 description 26
- 239000008215 water for injection Substances 0.000 description 26
- 238000002347 injection Methods 0.000 description 24
- 239000007924 injection Substances 0.000 description 24
- 239000003814 drug Substances 0.000 description 23
- 210000000959 ear middle Anatomy 0.000 description 23
- 239000000725 suspension Substances 0.000 description 23
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 22
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 239000000126 substance Substances 0.000 description 20
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 19
- 239000011521 glass Substances 0.000 description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 18
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 18
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 18
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 17
- 229930182566 Gentamicin Natural products 0.000 description 17
- 235000010980 cellulose Nutrition 0.000 description 17
- 229960002518 gentamicin Drugs 0.000 description 17
- 239000012528 membrane Substances 0.000 description 17
- 230000005779 cell damage Effects 0.000 description 16
- 208000037887 cell injury Diseases 0.000 description 16
- 239000007788 liquid Substances 0.000 description 16
- 229920000428 triblock copolymer Polymers 0.000 description 16
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 15
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 15
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 15
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 229920001213 Polysorbate 20 Polymers 0.000 description 14
- 239000000463 material Substances 0.000 description 14
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 14
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 239000011734 sodium Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 230000006378 damage Effects 0.000 description 13
- 235000014113 dietary fatty acids Nutrition 0.000 description 13
- 239000000194 fatty acid Substances 0.000 description 13
- 229930195729 fatty acid Natural products 0.000 description 13
- 230000001965 increasing effect Effects 0.000 description 13
- 229940068977 polysorbate 20 Drugs 0.000 description 13
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 12
- 108010016731 PPAR gamma Proteins 0.000 description 12
- 102000000536 PPAR gamma Human genes 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 12
- 239000002245 particle Substances 0.000 description 12
- 229960000281 trometamol Drugs 0.000 description 12
- 102000023984 PPAR alpha Human genes 0.000 description 11
- 108010028924 PPAR alpha Proteins 0.000 description 11
- GHUUBYQTCDQWRA-UHFFFAOYSA-N Pioglitazone hydrochloride Chemical compound Cl.N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 GHUUBYQTCDQWRA-UHFFFAOYSA-N 0.000 description 11
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 11
- 230000003115 biocidal effect Effects 0.000 description 11
- 239000001768 carboxy methyl cellulose Substances 0.000 description 11
- 229960002827 pioglitazone hydrochloride Drugs 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- 229960004586 rosiglitazone Drugs 0.000 description 11
- 229940032147 starch Drugs 0.000 description 11
- 230000035882 stress Effects 0.000 description 11
- 229940080774 Peroxisome proliferator-activated receptor gamma agonist Drugs 0.000 description 10
- 229920000436 Poly(lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly(lactide-co-glycolide) Polymers 0.000 description 10
- 206010061373 Sudden Hearing Loss Diseases 0.000 description 10
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 10
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 10
- 229940105329 carboxymethylcellulose Drugs 0.000 description 10
- 201000010099 disease Diseases 0.000 description 10
- 210000005069 ears Anatomy 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 229960003943 hypromellose Drugs 0.000 description 10
- 210000000067 inner hair cell Anatomy 0.000 description 10
- 210000000056 organ Anatomy 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 10
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 10
- 235000015424 sodium Nutrition 0.000 description 10
- 229910052708 sodium Inorganic materials 0.000 description 10
- 229960001641 troglitazone Drugs 0.000 description 10
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 10
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 description 10
- 239000003981 vehicle Substances 0.000 description 10
- 206010011903 Deafness traumatic Diseases 0.000 description 9
- 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 description 9
- 208000002946 Noise-Induced Hearing Loss Diseases 0.000 description 9
- 150000001298 alcohols Chemical class 0.000 description 9
- 239000003708 ampul Substances 0.000 description 9
- 239000003242 anti bacterial agent Substances 0.000 description 9
- 235000006708 antioxidants Nutrition 0.000 description 9
- 229950008138 carmellose Drugs 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 210000003477 cochlea Anatomy 0.000 description 9
- 150000004665 fatty acids Chemical class 0.000 description 9
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 9
- 210000004379 membrane Anatomy 0.000 description 9
- 238000004806 packaging method and process Methods 0.000 description 9
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 9
- 230000004044 response Effects 0.000 description 9
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 8
- 241000416162 Astragalus gummifer Species 0.000 description 8
- 206010011891 Deafness neurosensory Diseases 0.000 description 8
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 8
- 208000009966 Sensorineural Hearing Loss Diseases 0.000 description 8
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 8
- 239000013043 chemical agent Substances 0.000 description 8
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 8
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 8
- 208000035475 disorder Diseases 0.000 description 8
- 230000006870 function Effects 0.000 description 8
- 239000007789 gas Substances 0.000 description 8
- 229920001519 homopolymer Polymers 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 239000000178 monomer Substances 0.000 description 8
- 210000002985 organ of corti Anatomy 0.000 description 8
- 231100000879 sensorineural hearing loss Toxicity 0.000 description 8
- 208000023573 sensorineural hearing loss disease Diseases 0.000 description 8
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 8
- 238000001356 surgical procedure Methods 0.000 description 8
- CXGTZJYQWSUFET-IBGZPJMESA-N tesaglitazar Chemical compound C1=CC(C[C@H](OCC)C(O)=O)=CC=C1OCCC1=CC=C(OS(C)(=O)=O)C=C1 CXGTZJYQWSUFET-IBGZPJMESA-N 0.000 description 8
- 229950004704 tesaglitazar Drugs 0.000 description 8
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 8
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 7
- IRLWJILLXJGJTD-UHFFFAOYSA-N Muraglitazar Chemical compound C1=CC(OC)=CC=C1OC(=O)N(CC(O)=O)CC(C=C1)=CC=C1OCCC1=C(C)OC(C=2C=CC=CC=2)=N1 IRLWJILLXJGJTD-UHFFFAOYSA-N 0.000 description 7
- 229920001615 Tragacanth Polymers 0.000 description 7
- 239000002246 antineoplastic agent Substances 0.000 description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
- 235000019445 benzyl alcohol Nutrition 0.000 description 7
- 229960004217 benzyl alcohol Drugs 0.000 description 7
- 230000037396 body weight Effects 0.000 description 7
- ALEXXDVDDISNDU-JZYPGELDSA-N cortisol 21-acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ALEXXDVDDISNDU-JZYPGELDSA-N 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 238000013265 extended release Methods 0.000 description 7
- 229960000701 fenofibric acid Drugs 0.000 description 7
- MQOBSOSZFYZQOK-UHFFFAOYSA-N fenofibric acid Chemical compound C1=CC(OC(C)(C)C(O)=O)=CC=C1C(=O)C1=CC=C(Cl)C=C1 MQOBSOSZFYZQOK-UHFFFAOYSA-N 0.000 description 7
- 239000003349 gelling agent Substances 0.000 description 7
- 229950001135 muraglitazar Drugs 0.000 description 7
- 239000001301 oxygen Substances 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 7
- 238000011084 recovery Methods 0.000 description 7
- 235000010487 tragacanth Nutrition 0.000 description 7
- 239000000196 tragacanth Substances 0.000 description 7
- 229940116362 tragacanth Drugs 0.000 description 7
- 210000003454 tympanic membrane Anatomy 0.000 description 7
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- 208000027530 Meniere disease Diseases 0.000 description 6
- 239000004698 Polyethylene Substances 0.000 description 6
- 208000009205 Tinnitus Diseases 0.000 description 6
- 229930003427 Vitamin E Natural products 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 238000000540 analysis of variance Methods 0.000 description 6
- 239000003833 bile salt Substances 0.000 description 6
- 229940093761 bile salts Drugs 0.000 description 6
- 230000036760 body temperature Effects 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 229940127089 cytotoxic agent Drugs 0.000 description 6
- 230000009977 dual effect Effects 0.000 description 6
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 6
- 230000000670 limiting effect Effects 0.000 description 6
- 229920000573 polyethylene Polymers 0.000 description 6
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 6
- 231100000886 tinnitus Toxicity 0.000 description 6
- 239000011709 vitamin E Substances 0.000 description 6
- 235000019165 vitamin E Nutrition 0.000 description 6
- 229940046009 vitamin E Drugs 0.000 description 6
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 5
- 201000004384 Alopecia Diseases 0.000 description 5
- 239000005711 Benzoic acid Substances 0.000 description 5
- 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 5
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 5
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 5
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 5
- 229920006022 Poly(L-lactide-co-glycolide)-b-poly(ethylene glycol) Polymers 0.000 description 5
- 235000010233 benzoic acid Nutrition 0.000 description 5
- 210000000133 brain stem Anatomy 0.000 description 5
- 239000007853 buffer solution Substances 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 230000006727 cell loss Effects 0.000 description 5
- 230000000875 corresponding effect Effects 0.000 description 5
- 230000001419 dependent effect Effects 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 210000003060 endolymph Anatomy 0.000 description 5
- 239000002158 endotoxin Substances 0.000 description 5
- 239000012530 fluid Substances 0.000 description 5
- 230000003676 hair loss Effects 0.000 description 5
- 229920002674 hyaluronan Polymers 0.000 description 5
- 229960003160 hyaluronic acid Drugs 0.000 description 5
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 5
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 5
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 5
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 5
- 229920002521 macromolecule Polymers 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Chemical group OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 5
- 239000002798 polar solvent Substances 0.000 description 5
- 230000003449 preventive effect Effects 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 239000008174 sterile solution Substances 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 201000000200 vestibular neuronitis Diseases 0.000 description 5
- WMUIIGVAWPWQAW-DEOSSOPVSA-N (2s)-2-ethoxy-3-{4-[2-(10h-phenoxazin-10-yl)ethoxy]phenyl}propanoic acid Chemical compound C1=CC(C[C@H](OCC)C(O)=O)=CC=C1OCCN1C2=CC=CC=C2OC2=CC=CC=C21 WMUIIGVAWPWQAW-DEOSSOPVSA-N 0.000 description 4
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 4
- NMRWDFUZLLQSBN-UHFFFAOYSA-N 2,4-dichloro-n-(3,5-dichloro-4-quinolin-3-yloxyphenyl)benzenesulfonamide Chemical compound ClC1=CC(Cl)=CC=C1S(=O)(=O)NC(C=C1Cl)=CC(Cl)=C1OC1=CN=C(C=CC=C2)C2=C1 NMRWDFUZLLQSBN-UHFFFAOYSA-N 0.000 description 4
- HNLXNOZHXNSSPN-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CC(C)(C)CC(C)(C)C1=CC=C(OCCOCCOCCOCCOCCOCCOCCO)C=C1 HNLXNOZHXNSSPN-UHFFFAOYSA-N 0.000 description 4
- JJTUDXZGHPGLLC-IMJSIDKUSA-N 4511-42-6 Chemical compound C[C@@H]1OC(=O)[C@H](C)OC1=O JJTUDXZGHPGLLC-IMJSIDKUSA-N 0.000 description 4
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 4
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 229920000896 Ethulose Polymers 0.000 description 4
- 239000001859 Ethyl hydroxyethyl cellulose Substances 0.000 description 4
- 229920002683 Glycosaminoglycan Polymers 0.000 description 4
- 229920002907 Guar gum Polymers 0.000 description 4
- 229920000084 Gum arabic Polymers 0.000 description 4
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 229920002774 Maltodextrin Polymers 0.000 description 4
- 239000005913 Maltodextrin Substances 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- 108010015181 PPAR delta Proteins 0.000 description 4
- 101150014691 PPARA gene Proteins 0.000 description 4
- 229920001214 Polysorbate 60 Polymers 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 235000010489 acacia gum Nutrition 0.000 description 4
- 239000000205 acacia gum Substances 0.000 description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 235000010443 alginic acid Nutrition 0.000 description 4
- 229920000615 alginic acid Polymers 0.000 description 4
- 150000005215 alkyl ethers Chemical class 0.000 description 4
- 230000006907 apoptotic process Effects 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 4
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 4
- 239000004359 castor oil Substances 0.000 description 4
- 235000019438 castor oil Nutrition 0.000 description 4
- 230000003915 cell function Effects 0.000 description 4
- 239000002738 chelating agent Substances 0.000 description 4
- 229960004926 chlorobutanol Drugs 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- YHAIUSTWZPMYGG-UHFFFAOYSA-L disodium;2,2-dioctyl-3-sulfobutanedioate Chemical compound [Na+].[Na+].CCCCCCCCC(C([O-])=O)(C(C([O-])=O)S(O)(=O)=O)CCCCCCCC YHAIUSTWZPMYGG-UHFFFAOYSA-L 0.000 description 4
- 235000019326 ethyl hydroxyethyl cellulose Nutrition 0.000 description 4
- 238000011049 filling Methods 0.000 description 4
- 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 4
- 229940075507 glyceryl monostearate Drugs 0.000 description 4
- 239000001087 glyceryl triacetate Substances 0.000 description 4
- 235000013773 glyceryl triacetate Nutrition 0.000 description 4
- 235000010417 guar gum Nutrition 0.000 description 4
- 239000000665 guar gum Substances 0.000 description 4
- 229960002154 guar gum Drugs 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 230000006698 induction Effects 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 239000000787 lecithin Substances 0.000 description 4
- 235000010445 lecithin Nutrition 0.000 description 4
- 238000011866 long-term treatment Methods 0.000 description 4
- 229940035034 maltodextrin Drugs 0.000 description 4
- 229920000609 methyl cellulose Polymers 0.000 description 4
- 235000010981 methylcellulose Nutrition 0.000 description 4
- 239000001923 methylcellulose Substances 0.000 description 4
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 4
- 239000012454 non-polar solvent Substances 0.000 description 4
- 229920004905 octoxynol-10 Polymers 0.000 description 4
- 229920004914 octoxynol-40 Polymers 0.000 description 4
- 150000008105 phosphatidylcholines Chemical class 0.000 description 4
- 229940067605 phosphatidylethanolamines Drugs 0.000 description 4
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 4
- 150000003904 phospholipids Chemical class 0.000 description 4
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 4
- 229950008257 ragaglitazar Drugs 0.000 description 4
- 229940035049 sorbitan monooleate Drugs 0.000 description 4
- 235000011069 sorbitan monooleate Nutrition 0.000 description 4
- 239000001593 sorbitan monooleate Substances 0.000 description 4
- 238000011146 sterile filtration Methods 0.000 description 4
- 230000001954 sterilising effect Effects 0.000 description 4
- 238000004659 sterilization and disinfection Methods 0.000 description 4
- 150000003462 sulfoxides Chemical class 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 229960002622 triacetin Drugs 0.000 description 4
- 235000015112 vegetable and seed oil Nutrition 0.000 description 4
- 239000008158 vegetable oil Substances 0.000 description 4
- 229920001285 xanthan gum Polymers 0.000 description 4
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 3
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 3
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 3
- 244000215068 Acacia senegal Species 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 102000011690 Adiponectin Human genes 0.000 description 3
- 108010076365 Adiponectin Proteins 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 3
- 241000700198 Cavia Species 0.000 description 3
- 208000000781 Conductive Hearing Loss Diseases 0.000 description 3
- 206010010280 Conductive deafness Diseases 0.000 description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 description 3
- 102000005744 Glycoside Hydrolases Human genes 0.000 description 3
- 108010031186 Glycoside Hydrolases Proteins 0.000 description 3
- 229920000569 Gum karaya Polymers 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- OKJHGOPITGTTIM-DEOSSOPVSA-N Naveglitazar Chemical compound C1=CC(C[C@H](OC)C(O)=O)=CC=C1OCCCOC(C=C1)=CC=C1OC1=CC=CC=C1 OKJHGOPITGTTIM-DEOSSOPVSA-N 0.000 description 3
- 239000005642 Oleic acid Substances 0.000 description 3
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 3
- 229920001710 Polyorthoester Polymers 0.000 description 3
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 235000010323 ascorbic acid Nutrition 0.000 description 3
- 239000011668 ascorbic acid Substances 0.000 description 3
- 229960005070 ascorbic acid Drugs 0.000 description 3
- 229920001400 block copolymer Polymers 0.000 description 3
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 3
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 3
- 235000010418 carrageenan Nutrition 0.000 description 3
- 229920001525 carrageenan Polymers 0.000 description 3
- 239000000679 carrageenan Substances 0.000 description 3
- 229940113118 carrageenan Drugs 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 229920003086 cellulose ether Polymers 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 235000015165 citric acid Nutrition 0.000 description 3
- 229960001214 clofibrate Drugs 0.000 description 3
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 3
- 208000023563 conductive hearing loss disease Diseases 0.000 description 3
- 230000001186 cumulative effect Effects 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 238000009792 diffusion process Methods 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 229940088679 drug related substance Drugs 0.000 description 3
- 229950001279 elafibranor Drugs 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 235000010944 ethyl methyl cellulose Nutrition 0.000 description 3
- 210000002388 eustachian tube Anatomy 0.000 description 3
- 229960002297 fenofibrate Drugs 0.000 description 3
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229940014259 gelatin Drugs 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 229960003627 gemfibrozil Drugs 0.000 description 3
- AFLFKFHDSCQHOL-IZZDOVSWSA-N gft505 Chemical compound C1=CC(SC)=CC=C1C(=O)\C=C\C1=CC(C)=C(OC(C)(C)C(O)=O)C(C)=C1 AFLFKFHDSCQHOL-IZZDOVSWSA-N 0.000 description 3
- 229910001385 heavy metal Inorganic materials 0.000 description 3
- 238000002513 implantation Methods 0.000 description 3
- 208000037906 ischaemic injury Diseases 0.000 description 3
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 3
- 235000014655 lactic acid Nutrition 0.000 description 3
- 239000004310 lactic acid Substances 0.000 description 3
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 description 3
- 238000012423 maintenance Methods 0.000 description 3
- 239000001630 malic acid Substances 0.000 description 3
- 235000011090 malic acid Nutrition 0.000 description 3
- 210000001595 mastoid Anatomy 0.000 description 3
- 229910021645 metal ion Inorganic materials 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 229950003494 naveglitazar Drugs 0.000 description 3
- 210000003061 neural cell Anatomy 0.000 description 3
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 3
- 210000004049 perilymph Anatomy 0.000 description 3
- 229920003023 plastic Polymers 0.000 description 3
- 239000004033 plastic Substances 0.000 description 3
- 239000002745 poly(ortho ester) Substances 0.000 description 3
- 238000010149 post-hoc-test Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 230000008263 repair mechanism Effects 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 150000003873 salicylate salts Chemical class 0.000 description 3
- MRWFZSLZNUJVQW-DEOSSOPVSA-N saroglitazar Chemical compound C1=CC(C[C@H](OCC)C(O)=O)=CC=C1OCCN1C(C=2C=CC(SC)=CC=2)=CC=C1C MRWFZSLZNUJVQW-DEOSSOPVSA-N 0.000 description 3
- 229950006544 saroglitazar Drugs 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 235000010378 sodium ascorbate Nutrition 0.000 description 3
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 3
- 229960005055 sodium ascorbate Drugs 0.000 description 3
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 238000012453 sprague-dawley rat model Methods 0.000 description 3
- 229920001897 terpolymer Polymers 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 3
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 3
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
- NZJXADCEESMBPW-UHFFFAOYSA-N 1-methylsulfinyldecane Chemical compound CCCCCCCCCCS(C)=O NZJXADCEESMBPW-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- JVTIXNMXDLQEJE-UHFFFAOYSA-N 2-decanoyloxypropyl decanoate 2-octanoyloxypropyl octanoate Chemical compound C(CCCCCCC)(=O)OCC(C)OC(CCCCCCC)=O.C(=O)(CCCCCCCCC)OCC(C)OC(=O)CCCCCCCCC JVTIXNMXDLQEJE-UHFFFAOYSA-N 0.000 description 2
- AFENDNXGAFYKQO-UHFFFAOYSA-N 2-hydroxybutyric acid Chemical class CCC(O)C(O)=O AFENDNXGAFYKQO-UHFFFAOYSA-N 0.000 description 2
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 description 2
- CDOUZKKFHVEKRI-UHFFFAOYSA-N 3-bromo-n-[(prop-2-enoylamino)methyl]propanamide Chemical compound BrCCC(=O)NCNC(=O)C=C CDOUZKKFHVEKRI-UHFFFAOYSA-N 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 2
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 2
- SJZRECIVHVDYJC-UHFFFAOYSA-M 4-hydroxybutyrate Chemical compound OCCCC([O-])=O SJZRECIVHVDYJC-UHFFFAOYSA-M 0.000 description 2
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical compound O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 2
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 241001289435 Astragalus brachycalyx Species 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 2
- QCZAWDGAVJMPTA-RNFRBKRXSA-N ClC1=CC=CC(=N1)C1=NC(=NC(=N1)N[C@@H](C(F)(F)F)C)N[C@@H](C(F)(F)F)C Chemical compound ClC1=CC=CC(=N1)C1=NC(=NC(=N1)N[C@@H](C(F)(F)F)C)N[C@@H](C(F)(F)F)C QCZAWDGAVJMPTA-RNFRBKRXSA-N 0.000 description 2
- 241000252233 Cyprinus carpio Species 0.000 description 2
- 229930182843 D-Lactic acid Natural products 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UWTATZPHSA-N D-lactic acid Chemical compound C[C@@H](O)C(O)=O JVTAAEKCZFNVCJ-UWTATZPHSA-N 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 2
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 2
- 229920002884 Laureth 4 Polymers 0.000 description 2
- 229920000161 Locust bean gum Polymers 0.000 description 2
- 208000002720 Malnutrition Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- KPKZJLCSROULON-QKGLWVMZSA-N Phalloidin Chemical compound N1C(=O)[C@@H]([C@@H](O)C)NC(=O)[C@H](C)NC(=O)[C@H](C[C@@](C)(O)CO)NC(=O)[C@H](C2)NC(=O)[C@H](C)NC(=O)[C@@H]3C[C@H](O)CN3C(=O)[C@@H]1CSC1=C2C2=CC=CC=C2N1 KPKZJLCSROULON-QKGLWVMZSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920000954 Polyglycolide Polymers 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- 229920002385 Sodium hyaluronate Polymers 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229940123464 Thiazolidinedione Drugs 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 229940023476 agar Drugs 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- DAYKLWSKQJBGCS-NRFANRHFSA-N aleglitazar Chemical compound C1=2C=CSC=2C(C[C@H](OC)C(O)=O)=CC=C1OCCC(=C(O1)C)N=C1C1=CC=CC=C1 DAYKLWSKQJBGCS-NRFANRHFSA-N 0.000 description 2
- 229950010157 aleglitazar Drugs 0.000 description 2
- 229940072056 alginate Drugs 0.000 description 2
- 229920013820 alkyl cellulose Polymers 0.000 description 2
- 125000005233 alkylalcohol group Chemical group 0.000 description 2
- 238000001949 anaesthesia Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 229960000686 benzalkonium chloride Drugs 0.000 description 2
- 229960001950 benzethonium chloride Drugs 0.000 description 2
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 2
- 229960004365 benzoic acid Drugs 0.000 description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000004641 brain development Effects 0.000 description 2
- 230000003139 buffering effect Effects 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229940057850 carbomer copolymer type a Drugs 0.000 description 2
- 229940049638 carbomer homopolymer type c Drugs 0.000 description 2
- 229940082484 carbomer-934 Drugs 0.000 description 2
- 229940043234 carbomer-940 Drugs 0.000 description 2
- 229920003090 carboxymethyl hydroxyethyl cellulose Polymers 0.000 description 2
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 description 2
- 229960005361 cefaclor Drugs 0.000 description 2
- OKBVVJOGVLARMR-QSWIMTSFSA-N cefixime Chemical compound S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QSWIMTSFSA-N 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 229920002301 cellulose acetate Polymers 0.000 description 2
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 2
- 229960001927 cetylpyridinium chloride Drugs 0.000 description 2
- YMKDRGPMQRFJGP-UHFFFAOYSA-M cetylpyridinium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 YMKDRGPMQRFJGP-UHFFFAOYSA-M 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- KXKPYJOVDUMHGS-OSRGNVMNSA-N chondroitin sulfate Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](OS(O)(=O)=O)[C@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](C(O)=O)O1 KXKPYJOVDUMHGS-OSRGNVMNSA-N 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 239000011557 critical solution Substances 0.000 description 2
- 229960005168 croscarmellose Drugs 0.000 description 2
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 2
- 229940022769 d- lactic acid Drugs 0.000 description 2
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 2
- 229960003964 deoxycholic acid Drugs 0.000 description 2
- 230000001627 detrimental effect Effects 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000003292 diminished effect Effects 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 229960000878 docusate sodium Drugs 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid ester group Chemical class C(CCCCCCCCCCC)(=O)O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 210000000883 ear external Anatomy 0.000 description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 2
- 239000001761 ethyl methyl cellulose Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229920001002 functional polymer Polymers 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000012074 hearing test Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000000265 homogenisation Methods 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 229920013821 hydroxy alkyl cellulose Polymers 0.000 description 2
- 229950002194 hymetellose Drugs 0.000 description 2
- 230000001976 improved effect Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 239000010954 inorganic particle Substances 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 229940062711 laureth-9 Drugs 0.000 description 2
- PAZHGORSDKKUPI-UHFFFAOYSA-N lithium metasilicate Chemical compound [Li+].[Li+].[O-][Si]([O-])=O PAZHGORSDKKUPI-UHFFFAOYSA-N 0.000 description 2
- 229910052912 lithium silicate Inorganic materials 0.000 description 2
- 235000010420 locust bean gum Nutrition 0.000 description 2
- 239000000711 locust bean gum Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 230000001071 malnutrition Effects 0.000 description 2
- 235000000824 malnutrition Nutrition 0.000 description 2
- XJRBAMWJDBPFIM-UHFFFAOYSA-N methyl vinyl ether Chemical compound COC=C XJRBAMWJDBPFIM-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 2
- TXXHDPDFNKHHGW-UHFFFAOYSA-N muconic acid Chemical group OC(=O)C=CC=CC(O)=O TXXHDPDFNKHHGW-UHFFFAOYSA-N 0.000 description 2
- 210000003097 mucus Anatomy 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 208000015380 nutritional deficiency disease Diseases 0.000 description 2
- 229960002446 octanoic acid Drugs 0.000 description 2
- 231100000199 ototoxic Toxicity 0.000 description 2
- 230000002970 ototoxic effect Effects 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 239000005022 packaging material Substances 0.000 description 2
- SECPZKHBENQXJG-FPLPWBNLSA-N palmitoleic acid Chemical compound CCCCCC\C=C/CCCCCCCC(O)=O SECPZKHBENQXJG-FPLPWBNLSA-N 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 229920001277 pectin Polymers 0.000 description 2
- 235000010987 pectin Nutrition 0.000 description 2
- 239000001814 pectin Substances 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- ONJQDTZCDSESIW-UHFFFAOYSA-N polidocanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO ONJQDTZCDSESIW-UHFFFAOYSA-N 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 239000004584 polyacrylic acid Substances 0.000 description 2
- 229920001610 polycaprolactone Polymers 0.000 description 2
- 229920002338 polyhydroxyethylmethacrylate Polymers 0.000 description 2
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 2
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 150000004804 polysaccharides Chemical class 0.000 description 2
- 229950008882 polysorbate Drugs 0.000 description 2
- 229940113124 polysorbate 60 Drugs 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical compound CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000000284 resting effect Effects 0.000 description 2
- 238000007151 ring opening polymerisation reaction Methods 0.000 description 2
- 210000001191 round window ear Anatomy 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical group OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 150000004760 silicates Chemical class 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 229940005550 sodium alginate Drugs 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
- 239000000661 sodium alginate Substances 0.000 description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 2
- BTURAGWYSMTVOW-UHFFFAOYSA-M sodium dodecanoate Chemical compound [Na+].CCCCCCCCCCCC([O-])=O BTURAGWYSMTVOW-UHFFFAOYSA-M 0.000 description 2
- 229940083575 sodium dodecyl sulfate Drugs 0.000 description 2
- OABYVIYXWMZFFJ-ZUHYDKSRSA-M sodium glycocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 OABYVIYXWMZFFJ-ZUHYDKSRSA-M 0.000 description 2
- 229940010747 sodium hyaluronate Drugs 0.000 description 2
- 229940082004 sodium laurate Drugs 0.000 description 2
- 229940001584 sodium metabisulfite Drugs 0.000 description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 description 2
- 229910052911 sodium silicate Inorganic materials 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 description 2
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 2
- IWQPOPSAISBUAH-VOVMJQHHSA-M sodium;2-[[(2z)-2-[(3r,4s,5s,8s,9s,10s,11r,13r,14s,16s)-16-acetyl-3,11-dihydroxy-4,8,10,14-tetramethyl-2,3,4,5,6,7,9,11,12,13,15,16-dodecahydro-1h-cyclopenta[a]phenanthren-17-ylidene]-6-methylheptanoyl]amino]ethanesulfonate Chemical compound [Na+].C1C[C@@H](O)[C@@H](C)[C@@H]2CC[C@]3(C)[C@@]4(C)C[C@H](C(C)=O)/C(=C(C(=O)NCCS([O-])(=O)=O)/CCCC(C)C)[C@@H]4C[C@@H](O)[C@H]3[C@]21C IWQPOPSAISBUAH-VOVMJQHHSA-M 0.000 description 2
- FIWQZURFGYXCEO-UHFFFAOYSA-M sodium;decanoate Chemical class [Na+].CCCCCCCCCC([O-])=O FIWQZURFGYXCEO-UHFFFAOYSA-M 0.000 description 2
- VBJGJHBYWREJQD-UHFFFAOYSA-M sodium;dihydrogen phosphate;dihydrate Chemical compound O.O.[Na+].OP(O)([O-])=O VBJGJHBYWREJQD-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 235000010199 sorbic acid Nutrition 0.000 description 2
- 239000004334 sorbic acid Substances 0.000 description 2
- 229940075582 sorbic acid Drugs 0.000 description 2
- 210000001323 spiral ganglion Anatomy 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 210000000645 stria vascularis Anatomy 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 238000001248 thermal gelation Methods 0.000 description 2
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 2
- 229940033663 thimerosal Drugs 0.000 description 2
- 230000009974 thixotropic effect Effects 0.000 description 2
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 2
- 229960000984 tocofersolan Drugs 0.000 description 2
- 229930003799 tocopherol Natural products 0.000 description 2
- 235000010384 tocopherol Nutrition 0.000 description 2
- 239000011732 tocopherol Substances 0.000 description 2
- 229960001295 tocopherol Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- 239000003656 tris buffered saline Substances 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 235000010493 xanthan gum Nutrition 0.000 description 2
- 239000000230 xanthan gum Substances 0.000 description 2
- 229940082509 xanthan gum Drugs 0.000 description 2
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 1
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- UPHOPMSGKZNELG-UHFFFAOYSA-N 2-hydroxynaphthalene-1-carboxylic acid Chemical group C1=CC=C2C(C(=O)O)=C(O)C=CC2=C1 UPHOPMSGKZNELG-UHFFFAOYSA-N 0.000 description 1
- XLZYKTYMLBOINK-UHFFFAOYSA-N 3-(4-hydroxybenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC(C(=O)C=2C=CC(O)=CC=2)=C1 XLZYKTYMLBOINK-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- WZRJTRPJURQBRM-UHFFFAOYSA-N 4-amino-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide;5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1.COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 WZRJTRPJURQBRM-UHFFFAOYSA-N 0.000 description 1
- RJWBTWIBUIGANW-UHFFFAOYSA-N 4-chlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Cl)C=C1 RJWBTWIBUIGANW-UHFFFAOYSA-N 0.000 description 1
- 240000006409 Acacia auriculiformis Species 0.000 description 1
- 101100510959 Arabidopsis thaliana SSU2 gene Proteins 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 241001061264 Astragalus Species 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 238000012935 Averaging Methods 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000197194 Bulla Species 0.000 description 1
- HPNDXFWFALAENY-WIIYFNMSSA-N CCO[C@@H](CC1C=CC(OCC[n]2c(-c(cc3)ccc3SC)ccc2C)=CC1)C(O)=O Chemical compound CCO[C@@H](CC1C=CC(OCC[n]2c(-c(cc3)ccc3SC)ccc2C)=CC1)C(O)=O HPNDXFWFALAENY-WIIYFNMSSA-N 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- DQEFEBPAPFSJLV-UHFFFAOYSA-N Cellulose propionate Chemical compound CCC(=O)OCC1OC(OC(=O)CC)C(OC(=O)CC)C(OC(=O)CC)C1OC1C(OC(=O)CC)C(OC(=O)CC)C(OC(=O)CC)C(COC(=O)CC)O1 DQEFEBPAPFSJLV-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 206010050337 Cerumen impaction Diseases 0.000 description 1
- 241000206575 Chondrus crispus Species 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Chemical group OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 235000001815 DL-alpha-tocopherol Nutrition 0.000 description 1
- 239000011627 DL-alpha-tocopherol Substances 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 244000165918 Eucalyptus papuana Species 0.000 description 1
- 206010063602 Exposure to noise Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Chemical group OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 241000331546 Grubea cochlear Species 0.000 description 1
- 108010010234 HDL Lipoproteins Proteins 0.000 description 1
- 102000015779 HDL Lipoproteins Human genes 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 241001546602 Horismenus Species 0.000 description 1
- 108010003272 Hyaluronate lyase Proteins 0.000 description 1
- 102000001974 Hyaluronidases Human genes 0.000 description 1
- 108050009363 Hyaluronidases Proteins 0.000 description 1
- 102000009066 Hyaluronoglucosaminidase Human genes 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- SHBUUTHKGIVMJT-UHFFFAOYSA-N Hydroxystearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OO SHBUUTHKGIVMJT-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000027601 Inner ear disease Diseases 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- 235000000072 L-ascorbyl-6-palmitate Nutrition 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical group OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 208000017119 Labyrinth disease Diseases 0.000 description 1
- 229910007536 Li2Si2 Inorganic materials 0.000 description 1
- 208000009564 MELAS Syndrome Diseases 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- TXXHDPDFNKHHGW-CCAGOZQPSA-N Muconic acid Chemical group OC(=O)\C=C/C=C\C(O)=O TXXHDPDFNKHHGW-CCAGOZQPSA-N 0.000 description 1
- 101100478600 Mus musculus Ssuh2 gene Proteins 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 208000005141 Otitis Diseases 0.000 description 1
- 206010033078 Otitis media Diseases 0.000 description 1
- 102100026456 POU domain, class 3, transcription factor 3 Human genes 0.000 description 1
- 101710133393 POU domain, class 3, transcription factor 3 Proteins 0.000 description 1
- 235000021319 Palmitoleic acid Nutrition 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 241000935974 Paralichthys dentatus Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 108010009711 Phalloidine Proteins 0.000 description 1
- 229920002023 Pluronic® F 87 Polymers 0.000 description 1
- 229920002675 Polyoxyl Polymers 0.000 description 1
- 206010036626 Presbyacusis Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 229910052774 Proactinium Inorganic materials 0.000 description 1
- 101710097688 Probable sphingosine-1-phosphate lyase Proteins 0.000 description 1
- 102100037719 Protein SSUH2 homolog Human genes 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 239000004115 Sodium Silicate Substances 0.000 description 1
- 101710105985 Sphingosine-1-phosphate lyase Proteins 0.000 description 1
- 101710122496 Sphingosine-1-phosphate lyase 1 Proteins 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- FJWGYAHXMCUOOM-QHOUIDNNSA-N [(2s,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6s)-4,5-dinitrooxy-2-(nitrooxymethyl)-6-[(2r,3r,4s,5r,6s)-4,5,6-trinitrooxy-2-(nitrooxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-3,5-dinitrooxy-6-(nitrooxymethyl)oxan-4-yl] nitrate Chemical compound O([C@@H]1O[C@@H]([C@H]([C@H](O[N+]([O-])=O)[C@H]1O[N+]([O-])=O)O[C@H]1[C@@H]([C@@H](O[N+]([O-])=O)[C@H](O[N+]([O-])=O)[C@@H](CO[N+]([O-])=O)O1)O[N+]([O-])=O)CO[N+](=O)[O-])[C@@H]1[C@@H](CO[N+]([O-])=O)O[C@@H](O[N+]([O-])=O)[C@H](O[N+]([O-])=O)[C@H]1O[N+]([O-])=O FJWGYAHXMCUOOM-QHOUIDNNSA-N 0.000 description 1
- DOBHPCQULYVEKJ-UHFFFAOYSA-N [Na].[Na].[Na].[Na].[Li].[Li] Chemical compound [Na].[Na].[Na].[Na].[Li].[Li] DOBHPCQULYVEKJ-UHFFFAOYSA-N 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910052783 alkali metal Chemical group 0.000 description 1
- 150000001340 alkali metals Chemical group 0.000 description 1
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- KMJRBSYFFVNPPK-UHFFFAOYSA-K aluminum;dodecanoate Chemical compound [Al+3].CCCCCCCCCCCC([O-])=O.CCCCCCCCCCCC([O-])=O.CCCCCCCCCCCC([O-])=O KMJRBSYFFVNPPK-UHFFFAOYSA-K 0.000 description 1
- HSMXEPWDIJUMSS-UHFFFAOYSA-K aluminum;tetradecanoate Chemical compound [Al+3].CCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCC([O-])=O HSMXEPWDIJUMSS-UHFFFAOYSA-K 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 235000006533 astragalus Nutrition 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 231100000893 auditory nerve damage Toxicity 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 210000000721 basilar membrane Anatomy 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 229920000229 biodegradable polyester Polymers 0.000 description 1
- 239000004622 biodegradable polyester Substances 0.000 description 1
- IKCOOALACZVGLI-GNOQXXQHSA-K bis[[(z)-octadec-9-enoyl]oxy]alumanyl (z)-octadec-9-enoate Chemical compound [Al+3].CCCCCCCC\C=C/CCCCCCCC([O-])=O.CCCCCCCC\C=C/CCCCCCCC([O-])=O.CCCCCCCC\C=C/CCCCCCCC([O-])=O IKCOOALACZVGLI-GNOQXXQHSA-K 0.000 description 1
- 208000002352 blister Diseases 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 230000006931 brain damage Effects 0.000 description 1
- 231100000874 brain damage Toxicity 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 229960002129 cefixime Drugs 0.000 description 1
- 229920006217 cellulose acetate butyrate Polymers 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 229920001727 cellulose butyrate Polymers 0.000 description 1
- 229920006218 cellulose propionate Polymers 0.000 description 1
- 229920003174 cellulose-based polymer Polymers 0.000 description 1
- 229940106164 cephalexin Drugs 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 210000002939 cerumen Anatomy 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 238000012824 chemical production Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- SECPZKHBENQXJG-UHFFFAOYSA-N cis-palmitoleic acid Natural products CCCCCCC=CCCCCCCCC(O)=O SECPZKHBENQXJG-UHFFFAOYSA-N 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- 238000011278 co-treatment Methods 0.000 description 1
- 229940047766 co-trimoxazole Drugs 0.000 description 1
- 231100000890 cochlea damage Toxicity 0.000 description 1
- 210000000860 cochlear nerve Anatomy 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 102000048124 delta Opioid Receptors Human genes 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- PZWDHVKNXVLHOV-UHFFFAOYSA-K di(hexadecanoyloxy)alumanyl hexadecanoate Chemical compound [Al+3].CCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCC([O-])=O PZWDHVKNXVLHOV-UHFFFAOYSA-K 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical group CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229960003722 doxycycline Drugs 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 229940125542 dual agonist Drugs 0.000 description 1
- 239000003221 ear drop Substances 0.000 description 1
- 229940047652 ear drops Drugs 0.000 description 1
- 208000019258 ear infection Diseases 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 230000019439 energy homeostasis Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 229940031098 ethanolamine Drugs 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 229960004667 ethyl cellulose Drugs 0.000 description 1
- 229940125753 fibrate Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 238000012632 fluorescent imaging Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 210000002683 foot Anatomy 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid 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
- 229960003883 furosemide Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 230000005182 global health Effects 0.000 description 1
- 239000000174 gluconic acid Chemical group 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Chemical group 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 238000011554 guinea pig model Methods 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 210000002266 hair cells auditory Anatomy 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- XXMIOPMDWAUFGU-UHFFFAOYSA-N hexane-1,6-diol Chemical compound OCCCCCCO XXMIOPMDWAUFGU-UHFFFAOYSA-N 0.000 description 1
- PMYUVOOOQDGQNW-UHFFFAOYSA-N hexasodium;trioxido(trioxidosilyloxy)silane Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[O-][Si]([O-])([O-])O[Si]([O-])([O-])[O-] PMYUVOOOQDGQNW-UHFFFAOYSA-N 0.000 description 1
- 229960002773 hyaluronidase Drugs 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000001341 hydroxy propyl starch Substances 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
- 229940072106 hydroxystearate Drugs 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229910052909 inorganic silicate Inorganic materials 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 235000010494 karaya gum Nutrition 0.000 description 1
- 229940090589 keflex Drugs 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 235000021374 legumes Nutrition 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000007257 malfunction Effects 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 229920003087 methylethyl cellulose Polymers 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 208000022949 middle ear disease Diseases 0.000 description 1
- 230000009525 mild injury Effects 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004065 mitochondrial dysfunction Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 229910052605 nesosilicate Inorganic materials 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000009223 neuronal apoptosis Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 229940079938 nitrocellulose Drugs 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical group CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Chemical group CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000004762 orthosilicates Chemical class 0.000 description 1
- 229940125703 otic agent Drugs 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- 229940056211 paraffin Drugs 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000011129 pharmaceutical packaging material Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 238000006068 polycondensation reaction Methods 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229910052913 potassium silicate Inorganic materials 0.000 description 1
- 235000019353 potassium silicate Nutrition 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 208000009800 presbycusis Diseases 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 230000007420 reactivation Effects 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000000518 rheometry Methods 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000000263 scanning probe lithography Methods 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 230000009528 severe injury Effects 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 238000005549 size reduction Methods 0.000 description 1
- 210000002363 skeletal muscle cell Anatomy 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 235000019795 sodium metasilicate Nutrition 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- NTHWMYGWWRZVTN-UHFFFAOYSA-N sodium silicate Chemical compound [Na+].[Na+].[O-][Si]([O-])=O NTHWMYGWWRZVTN-UHFFFAOYSA-N 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 230000005477 standard model Effects 0.000 description 1
- 239000008117 stearic acid Chemical group 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 208000023088 sudden sensorineural hearing loss Diseases 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 229940072226 suprax Drugs 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 231100000057 systemic toxicity Toxicity 0.000 description 1
- 210000004233 talus Anatomy 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229920006029 tetra-polymer Polymers 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- RLQWHDODQVOVKU-UHFFFAOYSA-N tetrapotassium;silicate Chemical compound [K+].[K+].[K+].[K+].[O-][Si]([O-])([O-])[O-] RLQWHDODQVOVKU-UHFFFAOYSA-N 0.000 description 1
- POWFTOSLLWLEBN-UHFFFAOYSA-N tetrasodium;silicate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-][Si]([O-])([O-])[O-] POWFTOSLLWLEBN-UHFFFAOYSA-N 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 125000005591 trimellitate group Chemical group 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 230000001720 vestibular Effects 0.000 description 1
- 210000001213 vestibule labyrinth Anatomy 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 229940098697 zinc laurate Drugs 0.000 description 1
- 229940105125 zinc myristate Drugs 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- 229940057977 zinc stearate Drugs 0.000 description 1
- NVKSAUAQUPYOPO-UHFFFAOYSA-L zinc;decanoate Chemical compound [Zn+2].CCCCCCCCCC([O-])=O.CCCCCCCCCC([O-])=O NVKSAUAQUPYOPO-UHFFFAOYSA-L 0.000 description 1
- GPYYEEJOMCKTPR-UHFFFAOYSA-L zinc;dodecanoate Chemical compound [Zn+2].CCCCCCCCCCCC([O-])=O.CCCCCCCCCCCC([O-])=O GPYYEEJOMCKTPR-UHFFFAOYSA-L 0.000 description 1
- GBFLQPIIIRJQLU-UHFFFAOYSA-L zinc;tetradecanoate Chemical compound [Zn+2].CCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCC([O-])=O GBFLQPIIIRJQLU-UHFFFAOYSA-L 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 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
- A61K9/0046—Ear
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
- A61K9/10—Dispersions; Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
Definitions
- the present invention relates to pharmaceutical compositions comprising a PPAR agonist and an auris-acceptable gel for preventing or treating hearing loss and/or for preventing or inhibiting hair cell degeneration or hair cell death in a subject.
- Hearing loss is related to damage of auditory hair cells e.g. apoptosis of the hair cells as a consequence of e.g. a continuous stress situation or a traumatic event e.g. leading to the activation of inflammatory pathways.
- Hearing loss can be caused e.g. by a noise trauma, by a medical intervention, by ischemic injury, by a non specific stress leading to sudden hearing loss or by age or can be chemically induced, wherein the chemical induction is caused e.g. by an antibiotic or a chemotherapeutic agent.
- Child hearing loss might be caused by pre or post natal deficiencies in the energy homeostasis of the auditory cells. Hearing loss can also be caused by mitochondrial dysfunction. (C. M.
- Hair cells are fully differentiated and are not replaced after cell death (only a few thousand cells from birth). It is well described in the literature that after stress and damage of the hair cells, the cells can enter a resting state with no functionality related to the hearing process but remain viable. Approaches to stimulate development or regeneration of new hair cells e.g. by administering growth factors or by stem cell-based therapies in order to achieve disease modification bear the risk of pro-tumorigenic side-effects.
- Hearing impairment is a major global health issue with profound societal and economic impact affecting over 275 million people world- wide.
- the occurrence of hearing loss is rapidly rising, due to e.g. increasing noise exposure and aging populations.
- no approved pharmaceutical therapies available today the unmet medical need is very high.
- there is a need for providing effective methods for prevention and subsequent treatment of hearing loss which allow for immediate as well as long term maintenance of preventive and/or therapeutic effects.
- the present invention relates generally to pharmaceutical compositions comprising a PPAR agonist and an auris-acceptable gel for use in methods of preventing or treating hearing loss and methods of preventing or inhibiting hair cell degeneration or hair cell death.
- the present invention provides pharmaceutical compositions comprising a PPAR agonist and an auris- acceptable gel and methods which allow for protection of hair cells from stress e.g. from noise-induced stress, from surgery-induced stress, or from chemically-induced stress such as stress induced by an antibiotic or by a chemotherapeutic agent or from unspecific stress which may cause hearing loss.
- stress e.g. from noise-induced stress, from surgery-induced stress, or from chemically-induced stress such as stress induced by an antibiotic or by a chemotherapeutic agent or from unspecific stress which may cause hearing loss.
- a disadvantage of liquid pharmaceutical compositions for intratympanic injection is their propensity to drip into the eustachian tube causing rapid clearance of the composition from the inner ear.
- the pharmaceutical compositons provided herein comprise an auris-acceptable gel, most preferably a thermoreversible auris-acceptable gel, and, by virtue of said auris- acceptable gel, remain in contact with the target auditory surfaces (e.g., the round window) for extended periods of time. Accordingly, the pharmaceutical compositions described herein avoid attenuation of therapeutic benefit due to drainage or leakage of active agents (i.e. PPAR agonists) via the eustachian tube.
- active agents i.e. PPAR agonists
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising:
- auris-acceptable gel wherein the auris-acceptable gel comprises a compound selected from the group consisting of a copolymer comprising at least one hydrophilic block and/or at least one hydrophobic block, polyesters, colloidal silica, aluminum soaps, zinc soaps, natural gums, starch, cellulose and derivatives thereof, carboxyvinylpolymers, metal silicates and mixtures thereof,
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising:
- the auris-acceptable gel comprises a compound selected from the group consisting of a copolymer comprising at least one hydrophilic block and/or at least one hydrophobic block, polyesters, colloidal silica, aluminum soaps, zinc soaps, natural gums, starch, cellulose and derivatives thereof, carboxyvinylpolymers, metal silicates and mixtures thereof,
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising:
- the auris-acceptable gel comprises a compound selected from the group consisting of a copolymer comprising at least one hydrophilic block and/or at least one hydrophobic block, polyesters, colloidal silica, aluminum soaps, zinc soaps, natural gums, starch, cellulose and derivatives thereof, carboxyvinylpolymers, metal silicates and mixtures thereof.
- the present invention relates to a kit for preventing or treating hearing loss or preventing or inhibiting hair cell degeneration or hair cell death in a subject comprising a pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel described herein and instructions for using the kit.
- the present invention relates to a process for producing a pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel described herein, comprising the steps of:
- thermoreversible gel i. dissolving a thermoreversible gel in water for injection; ii. dissolving additional excipients in water for injection;
- Figure 2 shows the change in the average hearing thresholds in guinea pigs determined by auditory brainstem response (ABR) one week or two weeks after noise challenge vs. pre treatment values. Threshold shifts at individual frequencies were calculated for each animal by subtracting post-noise from pre-noise values. Group averages at each frequency were determined. An overall threshold shift was calculated for each treament group and timepoint by averaging the individual frequency shifts over 8 - 20 KHz. Data are mean ⁇ S.D. * p ⁇ 0.05.
- Figure 4 A-B show the efficacy of a pharmaceutical composition comprising a thermoreversible gel comprising pioglitazone to protect hearing from noise trauma.
- Vehicle treated animals showed a frequency-specific threshold shift of about 50-60 dB immediately after noise trauma.
- Pioglitazone significantly reduced the threshold shift in both experiments ( Figure 4 A,B).
- Animals treated 1 hr. after noise showed the greatest protection (approx. 20 dB across all frequencies).
- the treated ears had almost fully recovered, as evidenced by the return to pre-noise threshold values.
- Treatment 48 hr. after noise also reduced threshold shifts, but to a lesser extent compared to animals treated 1 hr. following noise trauma.
- the present invention provides pharmaceutical compositions comprising a PPAR agonist and an auris-acceptable gel for use in a method of preventing or treating hearing loss and/or for use in a method of preventing or inhibiting hair cell degeneration or hair cell death.
- PPAR agonist refers to a drug that is activating peroxisome proliferator activated receptor (PPAR) such as PPAR gamma receptor, PPAR alpha receptor, PPAR delta receptor or combinations thereof and includes PPAR gamma agonists such as e.g. pioglitazone, troglitazone or rosiglitazone, PPAR alpha agonists such as e.g. fibrates such as fenofibrate (fenofibric acid), clofibrate or gemfibrozil, PPAR dual agonists (PPAR
- PPAR gamma agonists such as e.g. pioglitazone, troglitazone or rosiglitazone
- PPAR alpha agonists such as e.g. fibrates such as fenofibrate (fenofibric acid), clofibrate or gemfibrozil
- PPAR dual agonists PPAR
- alpha/gamma or PPAR alpha/delta agonists such as e.g. aleglitazar, muraglitazar,
- PPAR delta agonists such as e.g. GW501516, PPAR pan agonists (PPAR alpha/delta/gamma agonist) or selective PPAR modulators such as e.g. INT131 and the pharmaceutically acceptable salts of these compounds.
- PPAR gamma agonists, PPAR modulators, PPAR alpha agonists and/or PPAR alpha/gamma dual agonists are used in the pharmaceutical compositions of the present invention, in particular PPAR gamma agonists, PPAR alpha agonists and/or PPAR
- alpha/gamma dual agonists are used in the pharmaceutical compositions of the present invention, more particularly PPAR gamma agonists selected from the group consisting of pioglitazone, rosiglitazone, troglitazone and pharmaceutically acceptable salts thereof, preferably pioglitazone or pharmaceutically acceptable salts thereof
- PPAR alpha agonists used in the pharmaceutical compositions of the present invention are selected from the group consisting of fenofibrate (fenofibric acid), clofibrate, gemfibrozil and pharmaceutically acceptable salts thereof, preferably fenofibrate (fenofibric acid) or pharmaceutically acceptable salts thereof
- PPAR alpha/gamma dual agonists used in the pharmaceutical compositions of the present invention are selected from the group consisting of aleglitazar, muraglitazar, tesaglitazar, ragaglitazar, saroglitazar, GFT505, naveglitazar or
- PPAR gamma agonists are used in the pharmaceutical compositions of the present invention, more preferably PPAR gamma agonists or modulators selected from the group consisting of pioglitazone, rosiglitazone, troglitazone, INT131 and pharmaceutically acceptable salts thereof, even more preferably PPAR gamma agonists selected from the group consisting of pioglitazone, rosiglitazone, troglitazone and pharmaceutically acceptable salts thereof are used. Even more preferably, pioglitazone or a pharmaceutically acceptable salt thereof, in particular pioglitazone hydrochloride is used in the pharmaceutical compositions of the present invention.
- micronized pioglitazone hydrochloride is used.
- a micronized PPAR agonist more preferably a micronized PPAR gamma agonist or modulator, even more preferably a micronized PPAR gamma agonist or modulator selected from the group consisting of micronized pioglitazone, micronized rosiglitazone, micronized troglitazone, micronized INT131 and pharmaceutically acceptable salts thereof, in particular a micronized PPAR gamma agonists selected from the group consisting of micronized pioglitazone, micronized rosiglitazone, micronized troglitazone and pharmaceutically acceptable salts thereof, more particular micronized pioglitazone and pharmaceutically acceptable salts thereof, most particular micronized pioglitazone hydrochloride is used in the pharmaceutical compositions of the present invention.
- a thiazolidinedione PPAR agonist is used in the pharmaceutical compositions of the invention.
- Suitable thiazolidinedione PPAR agonists are for example pioglitazone, troglitazone, rosiglitazone or pharmaceutically acceptable salts thereof.
- a particularly suitable thiazolidinone PPAR agonist is pioglitazone or a pharmaceutically acceptable salt thereof, in particular pioglitazone hydrochloride.
- Pioglitazone is described e.g. in US Patent No. 4,687,777 or in Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Lefebvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Koranyi L, Laakso M, Mokan M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Schemthaner G, Schmitz O, Skrha J, Smith U, Taton J; PROactive investigators. Lancet. 2005 Oct 8;366(9493): 1279-89, and is represented by the structural formula indicated below:
- Troglitazone is described e.g. in Florez JC, Jablonski KA, Sun MW, Bayley N, Kahn SE, Shamoon H, Hamman RF, Knowler WC, Nathan DM, Altshuler D; Diabetes Prevention Program Research Group. J Clin Endocrinol Metab. 2007 Apr;92(4): 1502-9 and is represented by the structural formula indicated below:
- Rosiglitazone is described e.g. in Nissen SE, Wolski K. N Engl J Med. 2007 Jun
- Clofibrate is described e.g. in Rabkin SW, Hayden M, Frohlich J. Atherosclerosis. 1988 Oct;73(2-3):233-40 and is represented by the structural formula indicated below:
- Fenofibrate (fenofibric acid) is described e.g. in Schima SM, Maciejewski SR, Hilleman DE, Williams MA, Mohiuddin SM. Expert Opin Pharmacother. 2010 Apr;l 1 (5):731 -8 and is represented by the structural formula indicated below:
- Gemfibrozil is described e.g. in Adabag AS, Mithani S, Al Aloul B, Collins D, Bertog S, Bloomfield HE; Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. Am Heart J. 2009 May; 157(5):913-8 and is represented by the structural formula indicated below:
- Aleglitazar is described e.g. in Lincoff AM, Tardif JC, Schwartz GG, Nicholls SJ, Ryden L, Neal B, Malmberg K, Wedel H, Buse JB, Henry RR, Weichert A, Cannata R, Svensson A, Volz D, Grobbee DE; AleCardio Investigators. JAMA. 2014 Apr 16;311(15): 1515-25 and is represented by the structural formula indicated below:
- Muraglitazar is described e.g. in Fernandez M, Gastaldelli A, Triplitt C, Hardies J, Casolaro A, Petz R, Tantiwong P, Musi N, Cersosimo E, Ferrannini E, DeFronzo RA. Diabetes Obes Metab. 2011 Oct;l3(l0):893-902 and is represented by the structural formula indicated below:
- Tesaglitazar is described e.g. in Bays H, McElhattan J, Bryzinski BS; GALLANT 6 Study Group. Diab Vase Dis Res. 2007 Sep;4(3): l8l-93 and is represented by the structural formula indicated below:
- Ragaglitazar is described e.g. in Saad MF, Greco S, Osei K, Lewin AJ, Edwards C, Nunez M, Reinhardt RR; Ragaglitazar Dose-Ranging Study Group. Diabetes Care. 2004
- Saroglitazar is described e.g. in Agrawal R. Curr Drug Targets. 2014 Feb;l5(2):l5l-5. and is represented by the structural formula indicated below:
- Naveglitazar is described e.g. in Ahlawat P, Srinivas NR. Eur J Drug Metab Pharmacokinet. 2008 Jul-Sep;33(3): 187-90.
- GW501516 is described e.g. in Wang X, Sng MK, Foo S, Chong HC, Lee WL, Tang MB, Ng KW, Luo B, Choong C, Wong MT, Tong BM, Chiba S, Loo SC, Zhu P, Tan NS. J Control Release. 2015 Jan 10; 197: 138-47 and is represented by the structural formula indicated below:
- GFT505 is described e.g. in Cariou B, Staels B. Expert Opin Investig Drugs. 2014
- INT131 is described e.g. in. Taygerly JP, McGee LR, Rubenstein SM, Houze JB, Cushing TD, Li Y, Motani A, Chen JL, Frankmoelle W, Ye G, Learned MR, Jaen J, Miao S,
- PPAR activation by the PPAR agonist is usually strong in the low nanomolar range to low micromolar range, e.g in a range of 0.1 nM to 100 mM.
- the PPAR activation is weak or partial, i.e. a PPAR agonist is used in the pharmaceutical compositions of the present invention which yields maximal activation of PPAR-receptor in a reporter assay system of 10% to 100% compared to a reference PPAR agonist which is known to cause a maximum PPAR activation.
- the preferred target for interaction of the PPAR agonist is the hair cell, which is most preferred; neural cells; and endothelial cells; and further includes adipocytes, hepatocytes, immune cells such as e.g. macrophages or dendritic cells, or skeletal muscle cells.
- hearing loss which is used herein interchangeably with the term“hearing impairment” refers to a diminished sensitivity to the sounds normally heard by a subject.
- the severity of a hearing loss is categorized according to the increase in volume above the usual level necessary before the listener can detect it.
- the term “hearing loss” as used herein includes sudden hearing loss (SHL) which is indicated in the literature also as“sudden sensorineural hearing loss (SSHL)”.
- SHL refers to illness which is characterized by a sudden, rapid sensorineural hearing loss mostly in one ear without obvious causes, normally accompanied with dizziness, and without vestibular symptomatology.
- SHL is defined as greater than 30 dB hearing reduction, over at least three contiguous frequencies, occurring over a period of 72 hours or less. SHL can be caused e.g. by unspecific stress.
- Hearing loss as referred herein is defined as a diminished ability to hear sounds like other people do. This can be caused either by conductive hearing loss, sensorineural hearing loss or a combination of both.
- Conductive hearing loss means that the vibrations are not passing through from the outer ear to the inner ear, specifically the cochlea. It can be due to an excessive build-up of earwax, glue ear, an ear infection with inflammation and fluid buildup, a perforated or defective eardrum, or a malfunction of the ossicles (bones in the middle ear). Sensorineural hearing loss is caused by dysfunction of the inner ear, the cochlea, auditory nerve, or brain damage.
- this kind of hearing loss is due to damage of the hair cells in the cochlea.
- Hearing loss as referred herein is usually sensorineural hearing loss or a combination of conductive hearing loss and sensorineural hearing loss.
- Sensorineural hearing loss can be related to age, to an acute or constant exposure to noise or chemicals, to a brain trauma or non specific stress which may lead to sudden hearing loss.
- hair cell degeneration refers to a gradual loss of hair cell function and integrity and/or leading ultimately to hair cell death.
- hair cell death refers to apoptosis of the hair cells in the inner ear.
- identification of hair cell damage or “ detection of hair cell damage” which are used interchangeably herein refer to a method by which the degree of hair cell damage in the inner ear can be determined. Such methods are known in the art and comprise for example fluorescent imaging of the hair cells, as described in the examples. An audiogram that demonstrates loss of hearing sensitivity at moderate to high frequencies is also indicative of hair cell damage. A decrease of hearing potential with no subsequent recovery is also diagnostic of hair cell damage.
- hearing loss or“hearing loss induced by a chemical” as referred herein refers to hearing loss which is induced and/or caused by chemical agents such as solvents, gases, paints, heavy metals, and/or medicaments which are ototoxic.
- sound pressure level or acoustic pressure level as referred herein is a logarithmic measure of the effective sound pressure of a sound relative to a reference value.
- Sound pressure level denoted L p and measured in dB, above a standard reference level, is given by:
- p rms is the root mean square sound pressure, measured in Pa
- po is the reference sound pressure, measured in Pa.
- the term "individual,” “subject” or “patient” are used herein interchangeably.
- the subject is a mammal. Mammals include, but are not limited to primates (including human and non- human primates). In a preferred embodiment, the subject is a human.
- % w/w refers to a mass fraction and is the ratio of one substance with mass rrij to the mass of the total pharmaceutical composition n3 ⁇ 4 0t with a denominator of 100, defined as: 100
- % w/V refers to a mass fraction and is the ratio of one substance with mass rrij to the volume of the total pharmaceutical composition (i.e. not just the volume of the solvent) V with a denominator of 100, defined as:
- % w/w x 100; wherein the unit of h 3 ⁇ 4 is in grams and wherein the unit of V is in mL.
- auris-acceptable gel includes a gel having no persistent detrimental effect on the auris media (or middle ear) and the auris interna (or inner ear) of the subject being treated.
- gel refers to semisolid systems consisting of either suspensions made up of small inorganic particles or large organic molecules interpenetrated by a liquid. Gels can consist of a single-phase or a two-phase system. A single-phase gel consists of organic macromolecules distributed uniformly throughout a liquid in such a manner that no apparent boundaries exist between the dispersed macromolecules and the liquid. Single-phase gels are usually prepared from e.g. synthetic macromolecules or from natural gums (e.g.
- Gels or jellies are semisolid systems consisting of suspensions of small inorganic particles or large organic molecules interpenetrated by a liquid. Gels are generally classified as a two-phase system, if the particle size of the dispersed phase is large; or as single phase gels, when the organic macromolecules are uniformly distributed throughout a liquid such that no apparent boundaries exist between the dispersed macromolecules and the liquid. Single- phase gels are preferred for use the present invention.
- gels can also be classified as being hydrophobic, hydrophilic or amphiphilic.
- Hydrophobic gels usually consist of a non-polar solvent such as liquid paraffin, polyethylene or fatty oils gelled with colloidal silica, or aluminum soaps or zinc soaps.
- hydrophilic gels usually consist of a polar solvent such as water, glycerol, or propylene glycol gelled with a suitable gelling agent (e.g., tragacanth, starch, cellulose and derivatives thereof, carboxyvinylpolymers, and/or magnesium-aluminum silicates).
- Amphiphilic gels usually consist of an amphiphilic copolymer having both hydrophilic and hydrophobic properties. Amphiphilic copolymers are prone to form micelles when brought in contact with a suitable solvent, e.g. water. Preferably, amphiphilic gels are used in the present invention.
- gelling agent refers to a compound that can be solubilized, dispersed or mixed with the pharmaceutical composition of the present invention to modify its rheological behaviour, more particularly its viscosity, and can lead to a higher viscosity composition or the formation of a hydrogel or the formation of a thermoreversible gel.
- gelling agents include, but are not limited to, celluloses, cellulose derivatives such as cellulose ethers (e.g., carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylcellulose, cellulose ethers (e.g., carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylcellulose,
- methylcellulose methylcellulose
- guar gum guar gum
- xanthan gum locust bean gum
- alginates e.g., alginic acid
- silicates starch
- tragacanth carboxyvinylpolymers
- carrageenan e.g., paraffin
- petrolatum e.g., petrolatum
- a preferred gelling agent is hydroxypropylmethylcellulose (Methocel®).
- thermogel refers to a gel having the ability to change from the liquid state to the gel state at temperatures close to body temperature, therefore allowing useful topical formulations.
- thermogel refers to a gel having the ability to change from the liquid state to the gel state at temperatures close to body temperature, therefore allowing useful topical formulations.
- thermogelling refers to a gel having the ability to change from the liquid state to the gel state at temperatures close to body temperature, therefore allowing useful topical formulations.
- thermogelling are used herein interchangeably in relation to a material which is liquid at lower temperature, but forms a viscous gel at a higher temperature. The process of thermogelling is fully reversible. Particularly preferred are thermoreversible gels comprising copolymers having a lower critical solution temperature (LCST) below 37°C.
- LCST critical solution temperature
- thermoreversible gels are water-soluble below their LCST, also known as gel temperature, due to strong hydrogen bonding between the hydrophilic part of the chains and water, but above the LCST value, hydrogen interactions are weakened and hydrophobic interactions between the hydrophobic domains of the polymer become dominant with consequent precipitation of the polymer resulting in gelation.
- the LCST value of a polymer depends on the balance of hydrophilic and hydrophobic portions of the copolymer and can be adjusted by varying this balance. It also depends on the concentration of the copolymer in water.
- thermoreversible gel is a gel comprising "ReGelTM", which is a tradename of MacroMed Inc. for a class of low molecular weight, biodegradable copolymers having reverse thermal gelation properties as described in U.S. Pat. Nos. 6,004,573; 6,117,949; 6,201,072, and 6,287,588.
- thermoreversible gel also includes biodegradable copolymers disclosed in U.S. patent application Ser. Nos. 09/906,041, 09/559,799 and 10/919,603.
- the biodegradable copolymers comprise ABA-type or BAB-type triblock copolymers or mixtures thereof, wherein the A-blocks are hydrophilic and comprise polyethylene glycol (PEG) and the B-b locks are hydrophobic and comprise biodegradable polyesters or poly(ortho ester)s, said copolymers having a hydrophobic content of between 50.1 to 83% by weight and a hydrophilic content of between 17 to 49.9% by weight, and an overall block copolymer molecular weight of between 2000 and 8000 daltons.
- the copolymers exhibit water solubility at temperatures below normal mammalian body temperatures and undergo reversible thermal gelation to a gel at temperatures equal to physiological mammalian body temperatures.
- the hydrophilic A-block segment is preferably polyethylene glycol (PEG) having an average molecular weight of between about 500 and 2200 daltons.
- the biodegradable, hydrophobic B polymer block comprises a polyester or poly(ortho ester), in which the polyester is synthesized from monomers selected from the group consisting of D,L-lactide, D-lactide, L-lactide, D,L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid, e-caprolactone, e-hydroxyhexanoic acid, g-butyro lactone, g- hydroxybutyric acid, d-valero lactone, d -hydroxyvaleric acid, hydroxybutyric acids, malic acid, and copolymers thereof and having an average molecular weight of between about 600 and 3000 Daltons.
- thermoreversible gel is a gel comprising a poloxamer.
- polyxamer refers to a copolymer composed of polyoxyethylene- polyoxypropylene copolymers.
- poloxamers include poloxamer 407 e.g.
- Kolliphor® P 407 (BASF Carp.), P407, Pluronic® F-127 (BASF Carp.), PF-127, Lutrol® F 127 (BASF Corp.) as described e.g. in the United States Pharmacopeia - National Formulary (USP/NF)), poloxamer 188 e.g. Kolliphor® P 188 BASF Corp., Pluronic® F-68 BASF Corp. as described e.g. in the United States Pharmacopeia - National Formulary (USP/NF)), poloxamer 237 e.g. Kolliphor® P 237 (BASF Corp.), Pluronic® F-87 (BASF Corp.)as described e.g.
- Poloxamer 407 has normally an Average Molecular Weight of 9,840 - 14,600 Da. Poloxamer 188 has normally an Average Molecular Weight of 7,680 - 9,510 Da. Poloxamer 237 has normally an Average Molecular Weight of 6,840 - 8,830 Da. Poloxamer 338 has normally an Average Molecular Weight of 12,700 - 17,400 Da. Pluronic ® F-127 is a commercially available polyoxyethylene-polyoxypropylene triblock copolymer (Poloxamer 407) with an Average Molecular Weight of 13,000 Da.
- Poloxamer 407 is of particular interest since concentrated aqueous solutions (20% w/w) of the copolymer are transformed from low viscosity transparent solutions to solid gels on heating to body temperature. Depending on additional components of a formulation, this transition temperature (LCST, lower critical solution temperature) or transition range may be achieved with distinctly lower concentrations of Poloxamer 407, e.g. with about 10 - 15% w/w. This phenomenon, therefore, suggests that when placed in contact with the body, the gel preparation will form a semi- so lid structure and an extended release depot. Furthermore, Poloxamer 407 has good solubilizing capacity, low toxicity and is, therefore, considered a good medium for drug delivery systems.
- LCST lower critical solution temperature
- thermoreversible gel is a gel comprising a PEG-PLGA- PEG triblock copolymer (wherein "PLGA” means polylactide-co-glycolide) (Jeong et al, J. Control. Release (2000), 63:155-63; Jeong et al, Adv. Drug Delivery Rev. (2002), 54:37-51).
- PLGA polylactide-co-glycolide
- the polymer exhibits sol-gel behavior over a concentration of about 5% w/w to about 40% w/w.
- the lactide/glycolide molar ratio in the PLGA copolymer can range from about 1 :1 to about 20:1.
- PEG-PLGA-PEG triblock copolymers are soluble in water and form a free-flowing liquid at room temperature, but form a hydrogel at body temperature.
- a commercially available PEG-PLGA-PEG triblock copolymer is RESOMER RGP t 50106 originally manufactured by Boehringer Ingelheim (now by Evonik Industries). This material is composed of a PLGA copolymer of 50:50 poly(DL-lactideco- glycolide) and is 10% w/w of PEG and has a molecular weight of about 6000 Da.
- polyethylene glycol polyethylene glycol
- PEG polyoxyethylene
- copolymer refers to polymers formed from two, three, four or more monomers.
- copolymer as used herein encompasses not only the basic copolymer of two monomers, but also terpolymers, tetrapolymers, pentapolymers and so forth.
- a copolymer is a copolymer made up of blocks of different polymerized monomers ("block copolymer”).
- block copolymer Copolymers in general and block copolymers in particular are commonly known in the art.
- Preferred copolymers are ABA-type or BAB-type triblock copolymers or mixtures thereof, wherein the A-blocks are hydrophilic and wherein the B- blocks are hydrophobic.
- hydrophilic refers to the common meaning of this term in the art, and denotes chemical moieties which comprise ionizable, polar, or polarizable atoms, or which otherwise may be solvated by water molecules.
- hydrophilic is typically used to describe materials that are capable of absorbing significant quantities of water, including those that are water-soluble.
- hydrophobic refers to the common meaning of this term in the art, and denotes non-polar chemical moieties which lack an affinity for water. Thus, the term “hydrophobic” is typically used to describe materials that are insoluble and non-swellable in water or an aqueous fluid.
- colloidal silica refers to Si0 2 particles in the micro-meter to nano- meter size range. Colloidal silica is described in the United States Pharmacopeia - National Formulary (USP/NF) under the designation Colloidal Silicon Dioxide. A hydrophobized version is described under the designation Hydrophobic Colloidal Silica. Commercially available products are AEROSILTM by Evonik Industries.
- soap refers to a salt of a fatty acid.
- fatty acid such as Zinc Laurate, Zinc Myristate, Zinc Stearate, Zinc
- aluminum soap refers to an aluminum salt of a fatty acid, such as as Aluminium Laurate, Aluminium Myristate, Aluminium Stearate, Aluminium Palmitate, Aluminium Oleate.
- starch as used herein includes com starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, hydroxypropylstarch and sodium carboxymethyl starch.
- cellulose derivative and “cellulosic polymer” are used herein interchangeably.
- cellulose derivative refers to a class of polymers derived from cellulose such as cellulose ethers, e.g. hydroxyalkyl celluloses and alkyl celluloses and cellulose esters.
- hydroxyalkyl celluloses include hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (hypromellose, HPMC), hydroxyethyl methyl cellulose (HEMC), ethyl hydroxyethyl cellulose (EHEC) and hydroxyethyl cellulose (HEC).
- alkyl celluloses include methyl cellulose and ethyl cellulose.
- the group of cellulose ethers further comprises carboxymethyl cellulose (carmellose), carboxymethyl hydroxyethyl cellulose (CMHEC) and sodium or calcium carmellose.
- carboxymethyl cellulose carboxymethyl cellulose
- CHEC carboxymethyl hydroxyethyl cellulose
- cellulose esters include nitro cellulose, cellulose acetate, cellulose butyrate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate and cellulose acetate trimellitate.
- a cellulosic polymer may also be both a cellulosic ether and a cellulosic ester, e.g. hydroxypropyl methylcellulose phthalate.
- cellulose derivatives as used herein further comprises cross-linked cellulosic polymers such as cross-linked carboxymethyl cellulose (croscarmellose) and sodium or calcium croscarmellose.
- cross-linked cellulosic polymers such as cross-linked carboxymethyl cellulose (croscarmellose) and sodium or calcium croscarmellose.
- croscarmellose cross-linked carboxymethyl cellulose
- sodium or calcium croscarmellose sodium or calcium croscarmellose.
- cellulose derivatives are preferred.
- Carboxyvinylpolymer refers to polyacrylic acid and the different Carbomer types (Carbomer Copolymer, Carbomer Homopolymer, Carbomer Interpolymer) as described e.g. in the United States Pharmacopeia - National Formulary (USP/NF).
- metal silicate as used herein inlcudes orthosilicates having the general formula M 4 Si0 4 , condensed noncyclic silicates having the general formula M 2n+2 Si n 0 3n+i , and metasilicates having the general formula M 2n Si n 0 3n wherein M is hydrogen or an alkali metal and n is an integer equal to or greater than one and preferably from one to three.
- the silicate additive to the electrolyte may be illustratively, sodium orthosilicate (Na 4 S1O 4 ) potassium orthosilicate (R 4 S1O 4 ), sodium pyrosilicate (Na 6 Si 2 0 7 ), potassium py rosilicate (R ⁇ S ⁇ CE), tetrasodium dilithium pyrosilicate (Na 4 Li 2 Si 2 0 7 ), silicic acid (H 2 S1O 3 ), sodium metasilicate (Na 2 Si0 3 ), potassium metasilicate (K 2 S1O 3 ), lithium metasilicate (LESiCE), sodium
- Metal silicates useful in the present invention comprise e.g magnesium aluminum silicate which, as used herein, refers to a compound having the chemical formula MgO-AfrCE-SiCE and which is a preferred metal silicate. Metal silicates are usually pharmaceutically acceptable metal silicates.
- naturally occuring gums comprising tragacanth, gum Arabic (e.g. gum Arabic powder), gum karaya, locust bean gum, carrageens, guar gum and xanthan gum.
- a particularly useful gum for the pharmaceutical compositions of the invention is tragacanth; a natural gum obtained from the dried sap of several species of Middle Eastern legumes of the genus Astragalus, including A. adscendens, A. gummifer, A. brachycalyx and A. tragacanthus.
- salts refers to a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
- Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxy-benzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane- disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
- a particularly preferred pharmaceutically acceptable salt is an acid addition salt formed with hydrochloric acid.
- Particle size is generally reported on a cumulative distribution by volume basis.
- the term "micronized” as used herein means particles with a median particle size, expressed by using the cumulative distribution by volume, of between about 1 pm and about 75 pm.
- 50 % of the particles (Dv50) of the micronized PPAR agonist as referred herein are smaller than or equal to about about 50 pm, more preferably smaller than or equal to about 10 pm, most preferably smaller than or equal to about 5 pm, in particular about 1 to about 10 pm, more particular about about 2 to about 8 pm, even more particular about 3 to about 5 pm, most particular about 4 pm.
- Micronization is a process of reducing the average diameter of particles of a solid material, whereby the particles are mostly passed through a jet mill.
- micronization is also used to maintain a narrow and consistent particle size distribution for any formulation described herein.
- a further purpose of micronization is to allow an easy application of the formulations of the invention by a parenteral syringe.
- the needle is wider than a 18 gauge needle.
- the needle gauge is from 18 gauge to 30 gauge.
- the needle is a 21 gauge needle.
- the gauge level of the syringe or hypodermic needle are varied accordingly.
- the formulations of the invention comprising micronized PPAR agonists are ejected e.g. from a 1 mL syringe adapted with a 50 mm length 21 G needle (nominal inner diameter 0.495 mm) without any plugging or clogging.
- solvent refers to a liquid substance capable of dispersing the other components of the composition.
- solvent as used herein further refers to polar and non-polar solvents and mixtures thereof. Solvents with a dielectric constant of less than 15 (at 0 °C) are generally considered to be nonpolar.
- Non-limiting examples of non-polar solvents are liquid paraffin, polyethylene and fatty oils.
- Non-limiting examples of polar solvents are water and alcohols, such as ethanol, glycerol, or propylene glycol.
- solvents used in the pharmaceutical composition of the invention are polar solvents such as water.
- surfactant refers to auris-acceptable compounds that lower the surface tension (or interfacial tension) between two liquids or between a liquid and a solid.
- Non-limiting examples of surfactants are sodium lauryl sulfate, sodium dioctyl sulfosuccinate (Docusate Sodium), polysorbates (e.g. products sold by Croda Int.
- Tween® Polysorbate 60 (Tween®60), Polysorbate 80 (Tween®80), Polysorbate 20 (Tween® 20)), triacetin, Vitamin E Polyethylene Glycol Succinate (Vitamin E TPGS), phospholipids, lecithins, phosphatidyl cholines (C8-C18), phosphatidylethanolamines (C8-C18),
- phosphatidylglycerols C8-C18
- sorbitan monooleate polyoxyethylene sorbitan monooleate
- bile salts glyceryl monostearate
- Preferred surfactants are polysorbates, e.g. polysorbate 80 and polysorbate 20.
- TweenTM20, Tween®60, Tween®80 as used herein refer to the corresponding Polysorbates as described e.g. in the United States Pharmacopeia - National Formulary (USP/NF).
- buffer refers to compositions well known to the skilled artisan that act to minimize the change in pH of a solution.
- Preferred buffers have a pKa that provides effective buffering at a pH of between about 6 and about 8, perferably buffering at a pH of between about 7 and about 8.
- Suitable buffers for use in the pharmaceutical composition of the invention include, but are not limited to trolamine hydrochloric acid buffer, acetate, bicarbonate, carbonate, ammonium chloride, citrate, phosphate, Tromethamine USP
- buffers for use in the pharmaceutical compositions of the invention are trolamine hydrochloric acid buffer and/or tromethamine.
- the pH of buffers used might be adjusted by adding a water diluted acid or base such as e.g by adding a diluted hydrochloric acid solution (10%) or adiluted sodium hydroxide solution (10%).
- trolamine refers to triethanolamine.
- trolamine hydrochloric acid buffer refers to a buffer containing trolamine adjusted to a particular pH with a solution containing between 9.5 g and 10.5 g Hydrochloric acid per 100 mL solution, preferably 10 g Hydrochloric acid per 100 mL solution (10% solution) .
- the pH of a trolamine hydrochloric acid buffer used in the present invention is between about 7 and about 8, preferably about 7.4.
- the pharmaceutical compositions of the invention have a pH that allows for terminal sterilization (e.g., by heat treatment and/or autoclaving) without degradation of the PPAR agonist and the auris-acceptable gel.
- the buffer pH is designed to maintain pH of the formulation in the 7-8 range at elevated temperatures. Any appropriate buffer is used depending on the particular PPAR agonist used in the formulation. Degradation of an otic agent may be reduced by the use of an appropriate combination of a buffer and polymeric additives (e.g. Poloxamer 407 or carboxymethyl celluose).
- permeability enhancer refers to chemical entities that facilitate transport of co-administered substances across biological membranes.
- permeability enhancer and “penetration enhancer” are used herein interchangeably.
- Permeability enhancers can be grouped according to chemical structure.
- Surfactants both ionic and non-ionic, such as sodium lauryl sulfate, sodium laurate, polyoxyethylene-20-cetyl ether, laureth-9, sodium dodecylsulfate, dioctyl sodium sulfo succinate, polyoxyethylene-9- lauryl ether (PLE), Tween 80, nonylphenoxypoly ethylene (NP-POE), polysorbates and the like, function as permeability enhancers.
- Bile salts such as sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium taurodihydrofusidate, sodium
- glycodihydrofusidate and the like fatty acids and derivatives thereof (such as oleic acid, caprylic acid, mono- and di-glycerides, lauric acids, acylcholines, caprylic acids,
- acylcamitines sodium caprates and the like
- chelating agents such as EDTA, citric acid, salicylates and the like
- sulfoxides such as dimethyl sulfoxide (DMSO), decylmethyl sulfoxide and the like
- alcohols such as ethanol, isopropanol, propylene glycol, polyethylene glycol, glycerol, propanediol, benzyl alcohol and the like
- Some enzymes, such as hyaluronidase and some glycosaminoglycans, such as hyaluronic acid also function as permeability enhancers.
- Preferred permeability enhancers are selected from the group consisting of benzyl alcohol, hyaluronic acid and pharmaceutically acceptable salts thereof and DMSO.
- Some gelling agents as commonly used in the preparation of hydrophobic and hydrophilic gels may also be used as viscosity increasing agents (thickening agents) and vice versa in the pharmaceutical compositions of the invention.
- some viscosity- increasing agents may be used as mucoadhesives and vice versa.
- a combination of a viscosity- increasing agent and a copolymer that is capable of forming a thermoreversible gel is used in the pharmaceutical compositions of the invention.
- viscosity-increasing agent includes, but is not limited to, hydroxypropyl methylcellulose (HPMC, hypromellose), hydroxyethyl cellulose, polyvinylpyrrolidone (PVP: povidone), carboxymethyl cellulose (carmellose), carboxymethylcellulose sodium, polyvinyl alcohol, sodium chondroitin sulfate, sodium hyaluronate, acacia (gum arabic), agar, sodium alginate, carbomer, carrageenan, carbopol, xanthan, gelatin, guar gum, maltodextrin, sterculia gum, polyethylene glycol (e.g.
- PEG 200-4500 tragacanth, ethylhydroxyethyl cellulose, ethylmethyl cellulose, methyl cellulose, hydroxyethylmethyl cellulose (hymetellose), hydroxypropyl cellulose, poly(hydroxyethyl methacrylate), pectin, methyl vinyl ether/maleic anhydride copolymer (PVM/MA), poly(methoxyethyl methacrylate),
- Particularly preferred viscosity- increasing agents are hypromellose and/or carbomer.
- Carbomer refers to certain polyacrylic acid derivatives (vide supra). It includes carbomer homopolymer (types A, B or C), carbomer copolymer (types A, B or C) and carbomer interpolymer (Types A, B or C). According to the USP/NF, the terms“A”,“B” or“C” refer to the viscosity of the corresponding Carbomer as follows:
- Carbopol refers to the different Carbomer products sold under the trade name Carbopol® by The Lubrizol Corporation.
- preservative as used herein is well known to the skilled artisan and refers to compounds that are used to kill or prevent growth of bacteria, yeast, and mold in the dosage form. Accordingly, preservatives are compounds that prevent or delay microbial activity (growth and metabolism). Suitable preservatives for use in the the pharmaceutical compositions of the invention include, but are not limited to, benzoic acid, p- hydroxybenzoates (e.g. methylparabene and propylparabene), benzyl alcohol, lower alkyl alcohols (e.g., ethanol, butanol or the like), Chlorobutanol, quaternary compounds (e.g.
- Benzalkonium Chloride Benzethonium Chloride, Cetylpyridinium Chloride
- sorbic acid Preferred preservatives are selected from the group consisting of benzoic acid, benzyl alcohol, chlorobutanol, p-hydroxybenzoates, methylparabene, and propylparabene, or combinations thereof, most preferably methylparabene, propylparabene, or combinations thereof.
- Suitable preservatives for use with a pharmaceutical composition of the invention are not ototoxic.
- mucoadhesive refers to compounds (typically polymers) that bind to the mucin layer of a biological membrane, i.e. increase the interaction of the
- compositions of the invention with a mucosal layer.
- mucoadhesives compounds should possess some general physiochemical features such as predominantly anionic hydrophilicity with numerous hydrogen bond forming groups, suitable surface property for wetting mucus/mucosal tissue surfaces and sufficient flexibility to penetrate the mucus network.
- the pharmaceutical compositions of the invention comprising a mucoadhesive adhere to the round window and/or the oval window and/or any inner ear structure.
- Mucoadhesive agents include, but are not limited to, soluble polyvinylpyrrolidone polymer (PVP); a water-swellable, but water-insoluble, fibrous, cross- linked carboxy- functional polymer; a crosslinked poly(acrylic acid) (e.g.
- Carbomer Copolymer Type A (PemulenTM TR-2 NF by Lubrizol Corp.), Carbomer Copolymer Type B (PemulenTM TR-l NF by Lubrizol Corp.)); a hydrophilic polysaccharide gum, maltodextrin, a cross-linked alginate gum gel, a water-dispersible poly carboxy lated vinyl polymer, or a mixture thereof.
- Mucoadhesive agents have been described, for example, in U.S. Pat. Nos. 6,638,521, 6,562,363, 6,509,028,
- antioxidant refers to a substance used as in vitro stabilizers of pharmaceutical preparations to mitigate oxidative processes. Antioxidants delay the onset of and/or significantly reduce the rate of complex oxidative reactions that could otherwise have a detrimental effect on the drug substance. Antioxidants also can be considered for protecting nonactive components such as unsaturated oils, pegylated lipids, flavors, and essential oils. Thus, antioxidants preserve the overall integrity of the dosage form against oxidative stress.
- Suitable antioxidants include acetylcysteine (N-acetyl-L-cysteine), ascorbic acid and sodium ascorbate, ascorbyl palmitate, benzyl alcohol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), glutathione, monothioglycerol, propyl gallate, sodium metabisulfite, sodium sulfite, tocopherol (e.g. dl-alpha-tocopherol) and the like, and suitable combinations of two or more hereof.
- the antioxidant is selected from the group consisting of ascorbic acid or sodium ascorbate, benzyl alcohol and monothioglycerol.
- liquid paraffin refers to a very highly refined mineral oil used in cosmetics and for medical purposes (definition according to the British Pharmacopoeia). Liquid paraffin is also known by its Latin name “paraffinum liquidum”.
- fatty oils refers to at room temperature liquid mixtures of mainly tri- and diglycerides of naturally occurring fatty acids, where the fatty acids are partially unsaturated with cis-configuration.
- unsaturated fatty acids are oleic acid, linoleic acid, palmitoleic acid, and arachidonic acid,
- prolonged release or“extended release” as used herein refer to release which is not immediate release, but release over a pre-defined, longer time period of up to several days, preferably over a period of more than 1 day, more preferably more than 2 days, more preferably more than 3 days, more preferably more than 4 days, more preferably more than 5 days, more preferably more than 6 days, more preferably 1 to 15 days, more preferably 2 to 12 days, more preferably 3 to 10 days, more preferably 4 to 7 days, more preferably 5 to 7 days, more preferably 6 to 7 days, most preferably 7 days.
- the present invention provides a pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel for use in a method of preventing or treating hearing loss in a subject.
- the present invention provides a method of preventing or treating hearing loss in a subject, which method comprises administering to the subject a pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel.
- the pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel is administered to the subject in an amount that is sufficient to prevent or treat hearing loss in the subject.
- the present invention provides the use of a pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel for the manufacture of a medicament for preventing or treating hearing loss in a subject.
- the present invention provides the use of a pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel for the manufacture of a medicament for preventing or treating hearing loss in a subject.
- the present invention provides the use of a pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel for the manufacture of a medicament for preventing or treating hearing loss in a subject.
- the present invention provides the use of a pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel for the manufacture of a medicament for preventing or treating hearing loss in a subject.
- composition comprising a PPAR agonist and an auris-acceptable gel for preventing or treating hearing loss in a subject.
- hearing loss to be prevented or treated by the pharmaceutical compositions of the present invention is caused by a noise trauma, by a medical intervention, by ischemic injury, by age or is chemically induced.
- the hearing loss can be thus a consequence of a medical intervention such as e.g. cochlear implantation.
- the chemical induction is usually caused by a chemical agent e.g. by an antibiotic or a chemotherapeutic agent.
- hearing loss is sudden hearing loss.
- Hearing loss caused by age comprises e.g. presbycusis.
- hearing loss caused by a noise trauma, cochlear implantation, or which is chemically induced, preferably by an antibiotic is prevented or treated by the pharmaceutical compositions of the present invention.
- hearing loss caused by a noise trauma or which is chemically induced, preferably by an antibiotic is prevented or treated by the pharmaceutical compositions of the present invention.
- hearing loss is of sensorineural origin caused by a damage leading to malnutrition of the cells in early brain development.
- early treatment with a PPAR agonist can be disease modifying preventing further damage.
- the pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel is administered before the subject has developed or before it is at risk to develop hearing loss, hair cell degeneration, hair cell death and/or a condition characterized by hair cell damage. In some embodiments, the pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel is administered after the subject has acquired hearing loss, hair cell degeneration, hair cell death and/or a condition characterized by hair cell damage. Further diseases, disorders or conditions which are related to, caused or characterized by hair cell degeneration and/or hair cell death and which can be prevented or treated by
- administering the pharmaceutical composition comprising a PPAR agonist and an auris- acceptable gel of the present invention are e.g. Meniere's disease, acute peripheral
- the present invention provides a pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel for use in a method of preventing or inhibiting hair cell degeneration or hair cell death in a subject, wherein hair cell degeneration or hair cell death is related to and/or caused by Meniere's disease, acute peripheral vestibulopathy and/or tinnitus.
- the present invention provides a pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel for use in a method of preventing or treating Meniere's disease in a subject.
- the present invention provides a method of preventing or treating Meniere's disease in a subject which method comprises administering to the subject a pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel.
- the present invention provides the use of a pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel for the manufacture of a medicament for preventing or treating Meniere's disease in a subject.
- the present invention provides the use of a pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel for preventing or treating Meniere's disease in a subject.
- the present invention provides a pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel for use in a method of preventing or treating acute peripheral vestibulopathy in a subject.
- the present invention provides a method of preventing or treating acute peripheral vestibulopathy in a subject which method comprises administering to the subject a pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel.
- the present invention provides the use of a pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel for the manufacture of a medicament for preventing or treating acute peripheral vestibulopathy in a subject. In some embodiments, the present invention provides the use of a pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel for preventing or treating acute peripheral vestibulopathy in a subject.
- the present invention provides a pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel for use in a method of preventing or treating tinnitus in a subject.
- the present invention provides a method of preventing or treating tinnitus in a subject which method comprises administering to the subject a pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel.
- the present invention provides the use of a pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel for the manufacture of a medicament for preventing or treating tinnitus in a subject.
- the present invention provides the use of a pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel for preventing or treating tinnitus in a subject.
- NIHL noise-induced hearing loss
- TTS temporary threshold shift
- PTS permanent threshold shift
- a noise trauma as referred herein is a noise trauma which is sufficient to cause damage to the organs of corti, in particular a noise trauma causing temporary or permanent hearing loss.
- a noise trauma can be caused by exposure to a sound pressure level of e.g., at least 70 dB (SPL), at least 90 dB (SPL), at least 100 dB (SPL), at least 120 dB (SPL) or at least 130 dB (SPL).
- Hearing loss can also be caused by a medical intervention usually by a medical intervention in the ear e.g. by cochlea surgery such as cochlear implantation.
- the pharmaceutical composition of the invention is administered before the subject is exposed to a noise trauma or medical intervention.
- the pharmaceutical composition of the invention is administered after the subject is exposed to a noise trauma or medical intervention.
- the pharmaceutical composition of the invention is administered prior to cochlear surgery i.e. before the subject undergoes cochlear surgery.
- Hearing loss caused by age also referred in the literature as“age-related hearing loss” is the cumulative effect of aging on hearing. It is normally a progressive bilateral symmetrical age- related sensorineural hearing loss. The hearing loss is most marked at higher frequencies. There are four pathological types of hearing loss caused by age:
- Hearing loss caused by age to be prevented or treated by the methods of the present invention is usually related to the first pathological type i.e. hearing loss characterised by degeneration of the organ of Corti.
- the pharmaceutical composition of the invention is administered to the subject prior to degeneration of the organ of Corti, e.g. prior to damage or apoptosis of hair cells and/or prior to hair cell degeneration or hair cell death.
- Hearing loss hair cell degeneration or hair cell death can be induced chemically i.e. by a chemical agent e.g. by an antibiotic, a drug, a chemotherapeutic agent, heavy metals or organic agents.
- Antibiotics which may cause hearing loss include for example cephalosporins such as cephalexin (Keflex), cefaclor (Ceclor), and cefixime (Suprax); aminoglycosides such as gentamicin, tobramycin and streptomycin; macrolides, such as erythromycin, azithromycin (Zithromax) and clarithromycin; sulfonamides such as trimethoprim-sulfamethoxazole or tetracylines such as tetracycline, or doxycycline.
- hair cell degeneration or hair cell death is effectively prevented or treated by the methods of the present invention in a subject exposed to gentamicin.
- Chemotherapeutic agents e.g. anti-cancer agents which may cause hearing loss, hair cell degeneration or hair cell death include for example platinum-containing agents e.g. cisplatin, and carboplatin, preferably cisplatin.
- Drugs which may cause hearing loss, hair cell degeneration or hair cell death include for example furosemide, quinine, aspirin and other salicylates.
- Heavy metals which may cause hearing loss include for example mercury, lead.
- Organic agents which may cause hearing loss, hair cell degeneration or hair cell death include for example toluene, xylene, or styrene.
- the pharmaceutical composition of the invention is administered to the subject before the subject is exposed to a chemical agent, thereby preventing the subject from chemically induced hearing loss, hair cell degeneration or hair cell death. In some embodiments the pharmaceutical composition of the invention is administered to the subject after the subject is exposed to a chemical agent thereby treating the subject having chemically induced hearing loss, hair cell degeneration or hair cell death.
- the pharmaceutical composition of the invention when hearing loss is caused by a noise trauma or is chemically induced, is administered to the subject prior to exposure of the subject to the noise trauma or to the chemical wherein at least 50%, preferably at least 60%, more preferably at least 70%, in particular at least 80%, more particular at least 90% of the cell damage of the hair cells caused by the noise trauma or the chemical agent is prevented.
- the present invention provides a pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel for use in a method of preventing or inhibiting hair cell degeneration or hair cell death in a subject.
- the present invention provides a method of preventing or inhibiting hair cell degeneration or hair cell death in a subject, which method comprises administering to the subject a pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel.
- the pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel is administered to the subject in an amount that is sufficient to prevent or inhibit hair cell degeneration or hair cell death in the subject.
- the present invention provides the use of a pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel for the manufacture of a medicament for preventing or inhibiting hair cell degeneration or hair cell death in a subject.
- the present invention provides the use of a pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel for preventing or inhibiting hair cell degeneration or hair cell death in a subject.
- hair cell degeneration or hair cell death in a subject is caused by a noise trauma, by age, a medical intervention, sudden hearing loss, or ischemic events such as ischemic injury, or is chemically induced wherein the chemical induction is caused by e.g. an antibiotic or a chemotherapeutic agent.
- Noise trauma, age, a medical intervention, sudden hearing loss, or ischemic events, or chemical induction can cause hair cell degeneration or hair cell death in a subject as described above for methods of preventing or treating hearing loss.
- hearing loss, hair cell degeneration or hair cell death is caused by hair cell damage.
- the pharmaceutical composition of the invention is administered to the subject prior to identification of said hair cell damage, i.e. prior to occurrence of hair cell damage.
- the pharmaceutical composition of the invention is administered to the subject prior to exposure of the subject to the noise trauma or to the chemical agent wherein at least 50%, preferably at least 60%, more preferably at least 70%, in particular at least 80%, more particular at least 90% of the cell damage of the hair cells caused by the noise trauma or the chemical agent is prevented.
- Identification/occurrence of hair cell damage is usually determined by evaluation of the state of the hair cells which can be easily accomplished as described above or as disclosed in the examples.
- compositions comprising a PPAR agonist and an auris-acceptable gel
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising: i. a PPAR agonist; and
- the auris-acceptable gel comprises a compound selected from the group consisting of a copolymer comprising at least one hydrophilic block and/or at least one hydrophobic block, polyesters, colloidal silica, aluminum soaps, zinc soaps, natural gums, starch, cellulose and derivatives thereof, carboxyvinylpolymers, metal silicates and mixtures thereof; and the use of this composition in a method of preventing or treating hearing loss and/or in a method of preventing or inhibiting hair cell degeneration or hair cell death in a subject.
- the pharmaceutical composition according to the invention comprises: i. a PPAR agonist; and
- auris-acceptable gel wherein the auris-acceptable gel comprises a compound selected from the group consisting of a copolymer comprising at least one hydrophilic block and/or at least one hydrophobic block, polyesters, colloidal silica, aluminum soaps, zinc soaps, natural gums, starch, cellulose derivatives, carboxyvinylpolymers, metal silicates and mixtures thereof; and
- said PPAR agonist is a PPAR gamma agonist, preferably a PPAR gamma agonist selected from the group consisting of pioglitazone, troglitazone, rosiglitazone and
- pharmaceutically acceptable salts thereof most preferably pioglitazone or a pharmaceutically acceptable salt thereof, in particular pioglitazone hydrochloride.
- the pharmaceutical composition according to the invention comprises: i. a PPAR agonist; and
- the auris-acceptable gel comprises a copolymer comprising at least one hydrophilic block and/or at least one hydrophobic block.
- said copolymer is present in an amount of about 5% to about 50% w/w, preferably of about 10% to about 30% w/w, more preferably of about 12.5% to about 25% w/w, most preferably of about 15% to about 20% w/w relative to the total weight of the pharmaceutical composition.
- said hydrophilic block is selected from the group consisting of polyethylene glycol (PEG), preferably PEG having an average molecular weight of between about 500 and 2200 daltons.
- said hydrophobic block is selected from the group consisting of a polyester, a poly(orthoester) and a polyoxypropylene. In a preferred embodiment, said hydrophobic blockis a polyoxypropylene. In a further embodiment, said hydrophobic block is a polyester, wherein said polyester is synthesized from monomers selected from the group consisting of D,L-lactide, D-lactide, L-lactide, D,L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid, e-caprolactone, e-hydroxyhexanoic acid, g-butyrolactone, g- hydroxybutyric acid, d-valero lactone, d -hydroxyvaleric acid, hydroxybutyric acids, malic acid, and copolymers thereof.
- said hydrophobic block is a polyester having an average molecular weight of between about 600 and 3000 daltons. In one embodiment, both said hydrophobic block and said hydrophilic block are biodegradable. In a preferred embodiment, the auris-acceptable gel comprised by the pharmaceutical
- compositions of the invention comprises a copolymer, wherein said copolymer is a PLGA- PEG-PLGA copolymer, preferably a PLGA-PEG-PLGA (1500-1000-1500) copolymer of the following formulas: a) ReGelTM
- X number of ethoxy units of the PEG part
- Y number of the lactic acid units of the PLGA part
- z number of glycolide units of the PLGA part
- the auris-acceptable gel comprised by the pharmaceutical compositions of the invention comprises a polyester, such as the polyesters comprised by AtriGelTM a polymeric (non-gelatin containing) delivery system consisting of a biodegradable poly (DL-lactide-co-glycolide) (PLGH or PLG) polymer formulation dissolved in a biocompatible solvent, N-methyl-2-pyrrolidone (NMP) and/or those disclosed, e.g. in U.S.
- AtriGelTM a polymeric (non-gelatin containing) delivery system consisting of a biodegradable poly (DL-lactide-co-glycolide) (PLGH or PLG) polymer formulation dissolved in a biocompatible solvent, N-methyl-2-pyrrolidone (NMP) and/or those disclosed, e.g. in U.S.
- the auris-acceptable gel comprised by the pharmaceutical compositions of the invention comprises a polyester selected from the group consisting of polylactides, polyglycolides, polycaprolactones, copolymers thereof, terpolymers thereof, and any combinations thereof.
- the auris-acceptable gel comprised by the pharmaceutical compositions of the invention comprises a polyester, wherein said polyester is 50/50 poly(DL- lactide-co-glycolide) having a carboxy terminal group; is present in about 30 wt. % to about 40 wt. % of the composition; and has an average molecular weight of about 23,000 to about 45,000.
- the said polyester is 75/25 poly (DL-lactide-co- glycolide) without a carboxy terminal group; is present in about 40 wt. % to about 50 wt. % of the composition; and has an average molecular weight of about 15,000 to about 24,000.
- the terminal groups of the poly(DL-lactide-co-glycolide) are either hydroxyl, carboxyl, or ester depending upon the method of polymerization.
- Polycondensation of lactic or glycolic acid provides a polymer with terminal hydroxyl and carboxyl groups.
- Ring-opening polymerization of the cyclic lactide or glycolide monomers with water, lactic acid, or glycolic acid provides polymers with the same terminal groups.
- ring-opening of the cyclic monomers with a mono functional alcohol such as methanol, ethanol, or l-dodecanol provides a polymer with one hydroxyl group and one ester terminal groups.
- Ring-opening polymerization of the cyclic monomers with a diol such as 1,6- hexanediol or polyethylene glycol provides a polymer with only hydroxyl terminal groups.
- the auris-acceptable gel comprised by the pharmaceutical compositions of the invention comprises a copolymer comprising at least one hydrophilic block and/or at least one hydrophobic block, wherein said hydrophilic block is polyethylene glycol and wherein said hydrophobic block is a polypropylene glycol.
- the auris-acceptable gel comprised by the pharmaceutical compositions of the invention comprises a copolymer, wherein said copolymer is a poloxamer.
- the average molar mass of the poloxamer is between about 6000 to about 18000 Da, more preferably between about 9000 to about 15000 Da.
- the auris-acceptable gel comprised by the
- compositions of the invention comprises a copolymer, wherein said copolymer is a poloxamer, preferably a poloxamer selected from the group consisting of poloxamer 407 (PF-127), poloxamer 188 (F-68 grade), poloxamer 237 (F-87 grade) and poloxamer 338 (F-108 grade).
- the auris-acceptable gel comprised by the pharmaceutical compositions of the invention comprises a copolymer, wherein said copolymer is poloxamer 407 (PF-127).
- the auris-acceptable gel comprised by the pharmaceutical compositions of the invention comprises a copolymer, wherein said copolymer is a PEG- PLGA-PEG triblock copolymer, preferably with a lactide/glycolide molar ratio in the PLGA block of from about 1 : 1 to about 20: 1.
- the auris-acceptable gel comprised by the pharmaceutical compositions of the invention comprises a copolymer, wherein said copolymer is a PEG-PLGA-PEG triblock copolymer having a 50:50 ratio of lactic acid and glycolic acid in the PLGA block and is 10% w/w of PEG and has a molecular weight of about 6000 ("RESOMER RGP t50l06" originally manufactured by Boehringer Ingelheim (now by Evonik Industries)).
- said copolymer is a PEG-PLGA-PEG triblock copolymer having a 50:50 ratio of lactic acid and glycolic acid in the PLGA block and is 10% w/w of PEG and has a molecular weight of about 6000 (“RESOMER RGP t50l06" originally manufactured by Boehringer Ingelheim (now by Evonik Industries)).
- the pharmaceutical composition of the invention comprises: i. about 0.1% to about 7.5% w/w of PPAR agonist, preferably a micronized PPAR agonist; and
- an auris-acceptable gel comprising about 10% w/w to about 30% w/w of a
- polyoxyethylene-polyoxypropylene copolymer preferably of poloxamer, in particular poloxamer 407, or of combinations of different polyoxyethylene- polyoxypropylene copolymers, or of combinations with further polymers.
- the pharmaceutical composition according to the invention comprises: i. a PPAR agonist; and
- auris-acceptable gel is a hydrophobic gel comprising a compound selected from the group consisting of colloidal silica, aluminum soaps and zinc soaps.
- the pharmaceutical composition according to the invention comprises: i. a PPAR agonist; and
- auris-acceptable gel is a hydrophilic gel comprising a compound selected from the group consisting of natural gums, starch, cellulose and derivatives thereof,
- the pharmaceutical composition according to the invention comprises: i. a PPAR agonist; and
- auris-acceptable gel is a thermoreversible gel comprising a compound selected from the group consisting of a copolymer comprising at least one hydrophilic block and/or at least one hydrophobic block and polyesters.
- the pharmaceutical composition according to the invention comprises: i. a PPAR agonist; and
- auris-acceptable gel is a thermoreversible gel comprising a compound selected from the group consisting of a copolymer comprising at least one hydrophilic block and/or at least one hydrophobic block.
- the pharmaceutical composition according to the invention comprises: i. a PPAR agonist; and
- auris-acceptable gel wherein the auris-acceptable gel comprises a polyester, preferably a polyester selected from the group consisting of polylactides, polyglycolides, polycaprolactones, copolymers thereof, terpolymers thereof, and any combinations thereof
- the auris-acceptable gel comprised by the
- compositions of the invention is a thermoreversible gel as defined herein.
- the rheology of the pharmaceutical composition of the invention is pseudo plastic, plastic, thixotropic, or diluent.
- the pharmaceutical composition of the invention comprises a solvent selected from the group consisting of liquid paraffin, polyethylene, fatty oils, water and alcohols (e.g. glycerol or propylene glycol).
- a solvent selected from the group consisting of liquid paraffin, polyethylene, fatty oils, water and alcohols (e.g. glycerol or propylene glycol).
- the pharmaceutical composition of the invention comprises a non polar solvent selected from the group consisting of liquid paraffin, polyethylene and fatty oils.
- the pharmaceutical composition of the invention comprises a polar solvent selected from the group consisting of water and alcohols (e.g. glycerol or propylene glycol).
- the pharmaceutical composition of the invention comprises a solvent, wherein said solvent is water.
- the pharmaceutical composition of the invention comprises a surfactant selected from the group consisting of polysorbates, cellulosic polymers and mixtures thereof.
- the pharmaceutical composition of the invention comprises a surfactant selected from the group consisting of sodium lauryl sulfate, sodium dioctyl sulfosuccinate (Docusate Sodium), polysorbates (e.g. the products sold by Croda Int. under the trade name TweenTM: Polysorbate 60 (Tween®60), Polysorbate 80 (Tween®80), Polysorbate 20 (Tween 20)), triacetin, Vitamin E Polyethylene Glycol Succinate, phospholipids, lecithins,
- said surfactant is a polysorbate, preferably polysorbate 80 or polysorbate 20, most preferably polysorbate 80.
- said surfactant is present in an amount of about 0.1% to about 5% w/w relative to the total weight of the pharmaceutical composition.
- a preferred range is about 0.75 to about 1.5% w/w relative to the total weight of the pharmaceutical composition, more preferably about 0.75 to about 1.25 % w/w, even more preferably about 1.0 % w/w.
- the pharmaceutical composition of the invention comprises a buffer comprising trolamine hydrochloric acid buffer, acetate, bicarbonate, carbonate, ammonium chloride, citrate, phosphate, Tromethamine (tris(hydroxymethyl)aminomethane (“TRIS”)), pharmaceutically acceptable salts thereof and/or combinations or mixtures thereof
- said buffer comprises a trolamine hydrochloric acid buffer.
- said buffer is a Tromethamine (TRIS) buffer.
- Buffer concentrations as used for parenteral formulations are in the range of 10 - 100 mMol/L.
- the absolute quantities of a specific buffer used in a parenteral formulation will therefore depend on the molecular weight of the selected buffer.
- said buffer is present in an amount of about 0.15% to about 1.5% w/w relative to the total weight of the pharmaceutical composition.
- a preferred range is about 0.3 to about 1.3% w/w, more preferred about 0.8 to about 1.1% w/w relative to the total weight of the pharmaceutical composition.
- the pharmaceutical composition of the invention comprises a further excipient selected from the group consisting of a permeability enhancer, a preservative, a viscosity-increasing agent, a mucoadhesive and an antioxidant.
- the pharmaceutical composition of the invention comprises a
- the pharmaceutical composition of the invention comprises a
- permeability enhancer selected from the group consisting of surfactants (ionic and non-ionic), bile salts, fatty acids and derivatives thereof, chelating agents, sulfoxides, alcohols, glycosidases and glycosaminoglycans.
- the pharmaceutical composition of the invention comprises a
- permeability enhancer selected from the group consisting of surfactants (ionic and non- ionic), bile salts, fatty acids and derivatives thereof, chelating agents, sulfoxides, alcohols, glycosidases and glycosaminoglycans; wherein
- said surfactants are selected from the group consisting of sodium lauryl sulfate, sodium laurate, polyoxyethylene-20-cetyl ether, laureth-9, sodium dodecylsulfate, dioctyl sodium sulfosuccinate, polyoxyethylene-9-lauryl ether (PLE), Tween 80, nonylphenoxypoly ethylene (NP-POE) and polysorbates; and wherein
- said bile salts are selected from the group consisting of sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium taurodihydrofusidate and sodium
- glycodihydrofusidate and wherein said fatty acids and derivatives thereof are selected from the group consisting of oleic acid, caprylic acid, mono- and di-glycerides, lauric acids, acylcholines, caprylic acids,
- said chelating agents are selected from the group consisting of EDTA, citric acid and salicylates; and wherein
- said sulfoxides are selected from the group consisting of dimethyl sulfoxide (DMSO) and decylmethyl sulfoxide; and wherein
- said alcohols are selected from the group consisting of ethanol, isopropanol, propylene glycol, polyethylene glycol, glycerol, propanediol and benzyl alcohol; and wherein
- glycosidases are selected from the group consisting of hyaluronidases; and wherein said glycosaminoglycans are selected from the group consisting of hyaluronic acid and pharmaceutically acceptable salts thereof
- said permeability enhancer is selected from the group consisting of benzyl alcohol, hyaluronic acid and pharmaceutically acceptable salts thereof and DMSO. In a particularly preferred embodiment, said permeability enhancer is benzyl alcohol.
- the pharmaceutical composition of the invention comprises a
- the pharmaceutical composition of the invention comprises a preservative selected from the group consisting of benzoic acid, p-hydroxybenzoates (e.g. methylparabene and propylparabene), benzyl alcohol, lower alkyl alcohols (e.g., ethanol, butanol or the like), Chlorobutanol, quaternary compounds (e.g. Benzalkonium Chloride, Benzethonium Chloride, Cetylpyridinium Chloride), thimerosal, sorbic acid.
- a preservative selected from the group consisting of benzoic acid, p-hydroxybenzoates (e.g. methylparabene and propylparabene), benzyl alcohol, lower alkyl alcohols (e.g., ethanol, butanol or the like), Chlorobutanol, quaternary compounds (e.g. Benzalkonium Chloride, Benzethonium Chloride, Cetylpyridinium Chloride),
- said preservative is selected from the group consisting of benzoic acid, benzyl alcohol, chlorobutanol, p-hydroxybenzoates, methylparabene, and propylparabene, or combinations thereof, most preferably methylparabene, propylparabene, or combinations thereof.
- the pharmaceutical composition of the invention comprises a viscosity- increasing agent.
- the pharmaceutical composition of the invention comprises a viscosity- increasing agent selected from the group consisting of hydroxypropyl methylcellulose (HPMC, hypromellose), hydroxyethyl cellulose, polyvinylpyrrolidone (PVP: povidone), carboxymethyl cellulose (carmellose), carboxymethylcellulose sodium, polyvinyl alcohol, sodium chondroitin sulfate, sodium hyaluronate, acacia (gum arabic), agar, sodium alginate, carbomer, carrageenan, carbopol®, xanthan, gelatin, guar gum, maltodextrin, sterculia gum, polyethylene glycol (e.g.
- PEG 200-4500 tragacanth, ethylhydroxyethyl cellulose, ethylmethyl cellulose, methyl cellulose, hydroxyethylmethyl cellulose (hymetellose), hydroxypropyl cellulose, poly(hydroxyethyl methacrylate), pectin, methyl vinyl ether/maleic anhydride copolymer (PVM/MA), poly(methoxyethyl methacrylate), poly(methoxyethoxyethyl methacrylate), Carboxymethylcellulose Sodium, silicon dioxide and combinations thereof.
- said viscosity- increasing agent is selected from the group consisting of hypromellose and a carbomer (e.g. carbomer homopolymer types A, B or C, carbomer copolymer types A, B or C or carbomer interpolymer types A, B or C).
- a carbomer e.g. carbomer homopolymer types A, B or C, carbomer copolymer types A, B or C or carbomer interpolymer types A, B or C.
- viscosity-increasing agents described herein are also utilized as gelling agents for forming the auris-acceptable gel comprised by the pharmaceutical composition of the invention.
- the auris-acceptable gel comprised by the pharmaceutical composition of the invention comprises a combination of a viscosity-increasing agent and a polymer capable of forming a thermoreversible gel as defined supra.
- Suitable combinations of viscosity- increasing agents and polymers capable of forming a thermoreversible gel include, by way of non-limiting example, a combination of poloxamer copolymers with cellulose based viscosity- increasing agents described herein.
- a secondary polymer e.g., a viscosity-increasing agent
- An appropriate viscosity-increasing agent e.g., a cellulose based polymer, e.g., Carmellose (carboxymethyl cellulose)
- a cellulose based polymer e.g., Carmellose (carboxymethyl cellulose)
- the selected secondary polymer e.g., Carmellose (carboxymethyl cellulose)
- the selected secondary polymer e.g., Carmellose (carboxymethyl cellulose)
- the ratio of a thermoreversible poloxamer to a gelling agent is about 50:1, about 40:1, about 35:1, about 30:1, about 25:1, about 20:1, about 15:1 or about 10:1.
- the pharmaceutical composition of the invention comprises a combination of poloxamer 407 (pluronic F127) and Carmellose (carboxymethyl cellulose) in a ratio of about 50:1, 40:1, about 35:1, about 30:1, about 25:1, about 20:1, about 15:1 or about 10: 1.
- the pharmaceutical composition of the invention comprises a mucoadhesive.
- the pharmaceutical composition of the invention comprises a mucoadhesive selected from the group consisting of soluble polyvinylpyrrolidone polymer (PVP); a water-swellable, but water-insoluble, fibrous, cross-linked carboxy- functional polymer; a crosslinked poly(acrylic acid) (e.g. Carbopol 947P, Carbopol 934P, Majithiya et al, AAPS PharmSciTech (2006), 7(3), p. El; EP0551626); a carbomer homopolymer (e.g.
- Carbomer 934 (CarbopolTM 934 NF by Lubrizol Corp.), Carbomer 940 (CarbopolTM 940 NF by Lubrizol Corp.), Carbomer 941 (CarbopolTM 941 NF by Lubrizol Corp.)); a carbomer copolymer (e.g.
- Carbomer Copolymer Type A (PemulenTM TR-2 NF by Lubrizol Corp.), Carbomer Copolymer Type B (PemulenTM TR-l NF by Lubrizol Corp.)); a hydrophilic polysaccharide gum, maltodextrin, a cross-linked alginate gum gel, a water- dispersible polycarboxylated vinyl polymer, or a mixture thereof.
- said mucoadhesive is a carbomer selected from the group consisting of Carbopol 947P and Carbopol 934P.
- the pharmaceutical composition of the invention comprises an
- the pharmaceutical composition of the invention comprises an antioxidant selected from the group consisting of sodium meta-bisulfite,
- EDTA ethylenediaminetetraacetic acid
- threof e.g. disodium EDTA
- sodium ascorbate sodium ascorbate
- ascorbic acid ascorbic acid palmitate
- BHT butylated hydroxytoluene
- benzyl alcohol e.g. alpha-tocopherol
- the pharmaceutical composition according to the invention comprises:
- a PPAR agonist preferably a micronized PPAR agonist
- the auris-acceptable gel comprises a copolymer comprising at least one hydrophilic block and/or at least one hydrophobic block; preferably a poloxamer; more preferably P407; and wherein said PPAR agonist is a PPAR gamma agonist, preferably a PPAR gamma agonist selected from the group consisting of pioglitazone, troglitazone, rosiglitazone and
- pharmaceutically acceptable salts thereof most preferably pioglitazone or a pharmaceutically acceptable salt thereof, in particular pioglitazone hydrochloride;
- said surfactant is selected from the group consisting of sodium lauryl sulfate, sodium dioctyl sulfo succinate, polysorbates (e.g. Tween®60, Tween®80, Tween ®20), triacetin, Vitamin E Polyethylene Glycol Succinate (Vitamin E TPGS), phospholipids, lecithins, phosphatidyl cholines (C8-C18), phosphatidylethanolamines (C8-C18), phosphatidylglycerols (C8-C18), sorbitan monooleate, polyoxyethylene sorbitan monooleatebile salts, glyceryl monostearate, polyoxyethylene fatty acid glycerides, vegetable oils (e.g., polyoxyethylene (60) hydrogenated castor oil), polyoxyethylene alkylethers and alkylphenyl ethers (e.g., octoxynol 10, oct
- said buffer is selected from the group consisting of a trolamine hydrochloric acid buffer, acetate, bicarbonate, carbonate, ammonium chloride, citrate, phosphate (e.g.
- PBS phosphate-buffered saline
- TRIS tris(hydroxymethyl)aminomethane
- pharmaceutically acceptable salts thereof and/or combinations or mixtures thereof preferably a trolamine hydrochloric acid buffer ; and
- said solvent is selected from the group consisting of liquid paraffin, polyethylene, fatty oils, water and alcohols (e.g. glycerol or propylene glycol); preferably water.
- the pharmaceutical composition according to the invention comprises:
- a PPAR agonist preferably a micronized PPAR agonist
- the auris-acceptable gel comprises about 10% w/w to about 20% w/w of a copolymer comprising at least one hydrophilic block and/or at least one hydrophobic block relative to the total weight of the pharmaceutical composition; preferably about 12% w/w to about 18% w/w of a poloxamer; more preferably about 14% w/w to about 16% w/w of P407; and wherein said PPAR agonist is a PPAR gamma agonist, preferably a PPAR gamma agonist selected from the group consisting of pioglitazone, troglitazone, rosiglitazone and
- pharmaceutically acceptable salts thereof most preferably pioglitazone or a pharmaceutically acceptable salt thereof, in particular pioglitazone hydrochloride;
- said surfactant is selected from the group consisting of sodium lauryl sulfate, sodium dioctyl sulfo succinate, polysorbates (e.g. Tween®60, Tween®80, Tween ®20), triacetin, Vitamin E Polyethylene Glycol Succinate (Vitamin E TPGS), phospholipids, lecithins, phosphatidyl cholines (C8-C18), phosphatidylethanolamines (C8-C18), phosphatidylglycerols (C8-C18), sorbitan monooleate, polyoxyethylene sorbitan monooleatebile salts, glyceryl monostearate, polyoxyethylene fatty acid glycerides, vegetable oils (e.g., polyoxyethylene (60) hydrogenated castor oil), polyoxyethylene alkylethers and alkylphenyl ethers (e.g., octoxynol 10, oct
- said buffer is selected from the group consisting of a trolamine hydrochloric acid buffer, acetate, bicarbonate, carbonate, ammonium chloride, citrate, phosphate, Tromethamine USP (tris(hydroxymethyl)aminomethane (TRIS), pharmaceutically acceptable salts thereof and/or combinations or mixtures thereof; preferably a trolamine hydrochloric acid buffer; and wherein said solvent is selected from the group consisting of liquid paraffin, polyethylene, fatty oils, water and alcohols (e.g. glycerol or propylene glycol); preferably water.
- a trolamine hydrochloric acid buffer acetate, bicarbonate, carbonate, ammonium chloride, citrate, phosphate, Tromethamine USP (tris(hydroxymethyl)aminomethane (TRIS), pharmaceutically acceptable salts thereof and/or combinations or mixtures thereof
- said solvent is selected from the group consisting of liquid paraffin, polyethylene, fatty oils, water and alcohols (e.g.
- the pharmaceutical composition of the invention comprises:
- pioglitazone i. pioglitazone or a pharmaceutically acceptable salt thereof, preferably
- micronized pioglitazone or a pharmaceutically acceptable salt thereof
- the auris-acceptable gel comprised by the pharmaceutical composition of the invention provides for an extended release of the PPAR agonist, preferably an extended release over a period of more than 1 day, more preferably more than 2 days, more preferably more than 3 days, more preferably more than 4 days, more preferably more than 5 days, more preferably more than 6 days, more preferably 1 to 15 days, more preferably 2 to 12 days, more preferably 3 to 10 days, more preferably 4 to 7 days, more preferably 5 to 7 days, more preferably 6 to 7 days, most preferably 7 days.
- the extended-release aspect is imparted by slow diffusion from the auris-acceptable gel and slow erosion of the auris-acceptable gel comprised by the pharmaceutical compositions of the invention, and by slow diffusion of the PPAR agonist from said auris-acceptable gel.
- the extended release aspect of the pharmaceutical compositions of the invention is imparted by said auris-acceptable gel and/or by an excipient selected from the group consisting of a viscosity- increasing agent, a mucoadhesive excipient and a mixture thereof.
- compositions described herein preferably provide for an extended release of a PPAR agonist, they may be
- a reduced frequency of administration alleviates discomfort caused by multiple intratympanic injections in individuals undergoing treatment for a middle and/or inner ear disease, disorder or condition.
- a reduced frequency of administration of intratympanic injections further reduces the risk of permanent damage (e.g., perforation) to the ear drum.
- the endolymph and the perilymph have a pH that is close to the physiological pH of blood.
- the endolymph has a pH range of about 7.2-7.9; the perilymph has a pH range of about 7.2-7.4.
- the in situ pH of the proximal endolymph is about 7.4 while the pH of distal endolymph is about 7.9.
- the pH of the pharmaceutical composition of the invention is adjusted (e.g., by use of a buffer) to an endolymph-compatible pH range of about 7.0 to 8.0, and a preferred pH range of about 7.2-7.9. In some embodiments, the pH of the pharmaceutical composition of the invention is adjusted (e.g., by use of a buffer) to a perilymph-compatible pH of about 7.0-7.6, and a preferred pH range of about 7.2-7.4.
- the pharmaceutical composition of the invention has at a temperature of 20°C a viscosity of below about 100 centipoise and allows for injection through the tympanic membrane with a 18-24 gauge needle. At 35°C, the same pharmaceutical composition shows a viscosity of between about 750 and 1,000,000 centipoise.
- the pharmaceutical composition of the invention is sterile (as determined by the methods described in the European Pharmacopoeia and/or the United States
- the pharmaceutical composition of the invention is submitted to a sterilization process.
- the presence of endotoxins is expressed in“endotoxin units” (EU).
- EU endotoxin units
- Humans can develop a response to as little as 5 EU/kg of body weight.
- the pharmaceutical compositions described herein contain lower endotoxin levels (e.g. ⁇ 4 EU/kg of body weight of a subject) when compared to conventionally acceptable endotoxin levels (e.g., 5 EU/kg of body weight of a subject).
- the pharmaceutical composition of the invention has less than about 5 EU/kg of body weight of a subject. In other embodiments, the pharmaceutical composition of the invention has less than about 4 EU/kg of body weight of a subject. In additional embodiments, the pharmaceutical composition of the invention has less than about 3 EU/kg of body weight of a subject. In additional embodiments, the pharmaceutical composition of the invention has less than about 2 EU/kg of body weight of a subject.
- the present invention relates to a process for producing a pharmaceutical composition comprising a PPAR agonist and an auris-acceptable gel described herein, comprising the steps of:
- thermoreversible gel i. dissolving a thermoreversible gel in water for injection
- sterile filter e.g a 0.22 pm filter
- micronized PPAR agonist in the sterile filtrate, using aseptic procedures; and vi. filling required quantities of the suspension into an appropriate packaging
- the process may be different, e.g. dissolution of the PPAR-agonist or its pharmaceutically acceptable salt in the aqueous phase, filtration of the final solution to remove particles, ampoule filling and closing, and final thermal sterilization.
- a pharmaceutical composition according to the invention based on a poloxamer may be prepared as follows:
- Poloxamer is dissolved in a solution of a buffer in water for injection at a temperature of not more than lO°C.
- a solution of a surfactant in water is mixed with the poloxamer - buffer solution.
- the pH of the mixture may be adjusted by adding dilute hydrochloric acid or dilute sodium hoydroxide.
- the final solution is filtered through an appropriate membrane filter 0.2 pm to get a sterile material.
- micronized, sterile PPAR agonist is suspended and homogenized in the sterile filtrate.
- the sterile bulk product is filled into appropriate glass ampoules, which are closed by the well-known ampoule closing process based on a flame of mixed gas and oxygen to melt the glass.
- the pharmaceutical composition according to the invention comprises:
- auris-acceptable gel comprises a poloxamer
- a suitable poloxamer for use in the auris-acceptable gel (ii) is, for example, poloxamer 407.
- a suitable surfactant for use in the pharmaceutical composition is, for example, polysorbate 80 or polysorbate 20.
- a suitable buffer for use in the pharmaceutical composition is, for example, a TRIS or trolamine hydrochloric acid buffer .
- a suitable permeability enhancer for use in the pharmaceutical composition is, for example, benzyl alcohol.
- a pharmaceutical composition according to the invention based on a poloxamer and comprising a permeability enhancer may be prepared as follows:
- Poloxamer is dissolved in a solution of a buffer in water for injection at a temperature of not more than lO°C.
- a solution of a surfactant and a permeability enhancer in water is mixed with the poloxamer - buffer solution.
- the pH of the mixture may be adjusted by adding dilute hydrochloric acid or dilute sodium hoydroxide.
- the final solution is filtered through an appropriate membrane filter 0.2 pm to get a sterile material.
- micronized, sterile PPAR agonist is suspended and homogenized in the sterile filtrate.
- the sterile bulk product is filled into appropriate glass ampoules, which are closed by the well- known ampoule closing process based on a flame of mixed gas and oxygen to melt the glass.
- composition based on a combination of poloxamers
- the pharmaceutical composition according to the invention comprises: i. a PPAR agonist; and
- auris-acceptable gel comprises a combination of at least two poloxamers.
- the pharmaceutical composition according to the invention comprises:
- auris-acceptable gel comprises a combination of at least two poloxamers.
- a suitable combination of poloxamers for use in the auris-acceptable gel (ii) is, for example, a combination of poloxamer 407 and poloxamer 188.
- a suitable surfactant for use in the pharmaceutical composition is, for example, polysorbate 80 or polysorbate 20.
- a suitable buffer for use in the pharmaceutical composition is, for example, Tromethamine USP (TRIS) or a trolamine hydrochloric acid buffer USP/NF.
- a pharmaceutical composition according to the invention based on a combination of poloxamers may be prepared as follows: A combination of poloxamers is dissolved in a solution of a buffer in water for injection at a temperature of not more than lO°C. A solution of a surfactant in water is mixed with the poloxamer - buffer solution. The pH of the mixture may be adjusted by adding dilute hydrochloric acid or dilute sodium hydroxide. The final solution is filtered through an appropriate membrane filter 0.2 pm to get a sterile material. In a stepwise procedure, micronized, sterile PPAR agonist is suspended and homogenized in the sterile filtrate. The sterile bulk product is filled into appropriate glass ampoules, which are closed by the well- known ampoule closing process based on a flame of mixed gas and oxygen to melt the glass.
- composition based on a combination of a poloxamer and a cellulosic polymer
- the pharmaceutical composition according to the invention comprises: i. a PPAR agonist
- auris-acceptable gel comprises a poloxamer
- the pharmaceutical composition according to the invention comprises:
- auris-acceptable gel comprises a poloxamer
- a suitable poloxamer for use in the auris-acceptable gel (ii) is, for example, poloxamer 407.
- a suitable cellulosic polymer for use in the pharmaceutical composition is, for example, hypromellose.
- a suitable surfactant for use in the pharmaceutical composition is, for example, polysorbate 80 or polysorbate 20.
- a suitable buffer for use in the pharmaceutical composition is, for example, a TRIS.
- a pharmaceutical composition according to the invention based on a combination of a poloxamer and a cellulosic polymer may be prepared as follows: A cellulosic polymer is dispersed in hot water for injection and dissolved on cooling. After cooling, this solution is added to a solution of a poloxamer in a solution of a buffer in water for injection at a temperature of not more than lO°C. A solution of a surfactant in water is mixed with the poloxamer - buffer solution. The pH of the mixture may be adjusted by adding dilute hydrochloric acid or dilute sodium hoydroxide. The final solution is filtered through an appropriate membrane filter 0.2 pm to get a sterile material.
- micronized, sterile PPAR agonist is suspended and homogenized in the sterile filtrate.
- the sterile bulk product is filled into appropriate glass ampoules, which are closed by the well-known ampoule closing process based on a flame of mixed gas and oxygen to melt the glass.
- the process may be different, e.g. dissolution of the PPAR-agonist in the aqueous phase, filtration of the final solution to remove particles, ampoule filling and closing, and final thermal sterilization.
- composition based on a combination of poloxamers and a carbomer
- the pharmaceutical composition according to the invention comprises: i. a PPAR agonist
- auris-acceptable gel comprises a combination of at least two poloxamers.
- the pharmaceutical composition according to the invention comprises:
- auris-acceptable gel comprises a combination of at least two poloxamer and a carbomer.
- the at least two poloxamers for use in the auris-acceptable gel (ii) are preferably poloxamer 407, poloxamer 188.
- Suitable carbomers for use in the pharmaceutical composition are carbomer homopolymers (types A, B or C), carbomer copolymers (types A, B or C) and carbomer interpolymers (types A, B or C).
- a suitable surfactant for use in the pharmaceutical composition is, for example, polysorbate 80 or polysorbate 20.
- a suitable buffer for use in the pharmaceutical composition is, for example, a TRIS buffer.
- a pharmaceutical composition according to the invention based on a combination of poloxamers and a carbomer may be prepared as follows:
- a solution of poloxamers in water for injection at a temperature of not more than l0°C is prepared.
- a second solution of a surfactant and a buffer in water for injection is prepared and added to the Poloxamer solution.
- the combined solution is filtered through an appropriate membrane filter to get a sterile material.
- a sterile carbomer and micronized, sterile PPAR agonist are suspended and homogenized in the sterile filtrate.
- the sterile bulk product is filled into appropriate glass ampoules, which are closed by the well- known ampoule closing process based on a flame of mixed gas and oxygen to melt the glass.
- the process may be adapted, e.g. dissolution of the non-sterile PPAR-agonist in the aqueous phase, followed by sterile filtration and aseptic homogenization of the carbomer in the sterile filtrate.
- composition based on a combination of a poloxamer and a cellulosic polymer and comprising a mucoadhesive
- the pharmaceutical composition according to the invention comprises: i. a PPAR agonist
- auris-acceptable gel comprises a poloxamer
- the pharmaceutical composition according to the invention comprises:
- a cellulosic polymer iii. a cellulosic polymer; iv. a mucoadhesive;
- auris-acceptable gel comprises a poloxamer
- a suitable poloxamer for use in the auris-acceptable gel (ii) includes poloxamer 407.
- a suitable cellulosic polymer for use in the pharmaceutical composition includes
- Suitable mucoadhesives for use in the pharmaceutical composition are carbomers, in particular carbopol 934P.
- a suitable surfactant for use in the pharmaceutical composition is, for example, polysorbate 80 or polysorbate 20.
- a suitable buffer for use in the pharmaceutical composition is, for example, Tromethamine USP (tris(hydroxymethyl)aminomethane,“TRIS”) or a trolamine hydrochloric acid buffer .
- a suitable preservative for use in the pharmaceutical composition is, for example,
- a pharmaceutical composition according to the invention based on a poloxamer and comprising a mucoadhesive may be prepared as follows:
- a cellulosic polymer is dispersed in hot water for injection and dissolved on cooling. After cooling, this solution is added to a solution of poloxamer in water for injection, prepared at a temperature of not more than l0°C.
- a second solution of a surfactant, a preservative, a buffer, and a mucoadhesive is prepared in water for injection at room temperature. The two solutions are mixed. The pH of the mixture may be adjusted by adding, for example, dilute hydrochloric acid.
- the final solution is filtered through an appropriate membrane filter to get a sterile material.
- micronized, sterile PPAR agonist is suspended and homogenized in the sterile filtrate.
- the sterile bulk product is filled into appropriate glass ampoules, which are closed by the well-known ampoule closing process based on a flame of mixed gas and oxygen to melt the glass.
- the process may be adapted, e.g. dissolution of the non-sterile PPAR-agonist in the aqueous phase, followed by sterile filtration, and aseptic homogenization of e.g. a carbomer in the sterile filtrate.
- composition based on a combination of a PLGA-PEG- PLGA triblock copolymer
- the pharmaceutical composition according to the invention comprises:
- auris-acceptable gel comprises a PLGA-PEG- PLGA triblock copolymer.
- the pharmaceutical composition according to the invention comprises:
- auris-acceptable gel comprises a PLGA-PEG- PLGA triblock copolymer.
- Suitable copolymers for use in the auris-acceptable gel (ii) include ReGelTM PLGA-PEG- PLGA triblock copolymer, PolyVivo AK12TM, and PolyVivoAK24TM PLGA-PEG- PLGA triblock copolymers.
- a suitable surfactant for use in the pharmaceutical composition is, for example, polysorbate
- a suitable buffer for use in the pharmaceutical composition is, for example, a Tromethamine (tris(hydroxymethyl)aminomethane, TRIS) buffer.
- a pharmaceutical composition according to the invention based on a poloxamer and comprising a mucoadhesive may be prepared as follows:
- a solution of a surfactant and the PLGA-PEG- PLGA triblock copolymer in water (I st part) is prepared.
- Micronized PPAR agonist is suspended in this solution.
- a buffer solution in water (2 nd part) is added to adjust the pH.
- Water (3 rd part) is added to get the final concentration of 1.5 % of pioglitazone hydrochloride.
- the pharmaceutical composition described herein is usually administered topically in the ear or by injection into the inner ear and/or into the middle ear, preferably by injection into the middle ear.
- the auris-acceptable gel comprised by the pharmaceutical compositon of the invention is a thermoreversible gel and is administered by intratympanic injection at or near room temperature.
- the pharmaceutical compositions of the invention are liquid as long as stored in the primary container at a temperature below body temperature (typically at or below room temperature) or when handled by the clinician, but rapidly form a gel once injected into e.g. the middle ear cavity (temperature of about 37°C).
- the pharmaceutical composition of the invention is injected intratympanically and forms a gel layer over the round window. This has two inter-related effects: a) in contrast to conventional solutions or suspensions, the product remains in the middle ear; it is therefore not rapidly cleared through the Eustachian tube; and b) the diffusion rate through the hydrated gel layer is reduced, thereby providing a sustained release.
- Otic administration of the pharmaceutical compositions of the invention avoid certain drawbacks sometimes associated with systemic administration of the PPAR agonist comprised by the compositions (e.g., hepatotoxicity, cardiotoxicity, gastrointestinal side effects, renal toxicity, low bioavailability of the drug in the endolymph or perilymph, variability in concentration of the drug in the middle and/or internal ear).
- localized administration in the ear allows a PPAR agonist to reach a target organ (e.g., inner ear) in the absence of systemic accumulation of said PPAR agonist.
- target organ e.g., inner ear
- administration to the ear provides a higher therapeutic index for a PPAR agonist that would otherwise have dose-limiting systemic toxicity.
- the pharmaceutical composition of the invention comprises a thermoreversible gel and is suitable for PPAR agonist delivery into the inner ear, including the cochlea and vestibular labyrinth; preferably with little or no systemic release of the PPAR agonist.
- a sustained release sytem can be used for some routes of administration.
- the penetration of the active ingredient is facilitated by permeability enhancers as e.g. benzyl alcohol, hyaluronic acid or DMSO (vide supra).
- permeability enhancers as e.g. benzyl alcohol, hyaluronic acid or DMSO (vide supra).
- a thixotropic or thermogeling formulation is used to enable a painless administration and forming a gel or a high viscous composition ensuring prolonged and continuous release of the active ingredient into the inner ear and/or into the middle ear.
- the PPAR agonist or the pharmaceutical composition can be located in contact with the crista fenestrae cochlea, the round window, the tympanic cavity, the tympanic membrane, the auris media or the auris externa.
- the pharmaceutical composition of the invention can be administered on or near the round window membrane via intratympanic injection.
- the pharmaceutical composition of the invention is administered on or near the round window or the crista fenestrae cochleae through entry via a post-auricular incision and surgical manipulation into or near the round window or the crista fenestrae cochleae area.
- the pharmaceutical composition of the invention is applied via syringe and needle, wherein the needle is inserted through the tympanic membrane and guided to the area of the round window or crista fenestrae cochleae.
- the pharmaceutical composition of the invention is then deposited on or near the round window or crista fenestrae cochleae for localized treatment.
- composition as described herein is administered by:
- Intratympanic injection of therapeutic agents is the technique of injecting an agent behind the tympanic membrane into the middle and/or inner ear, preferably into the middle ear.
- the pharmaceutical compositions described herein are administered directly onto the round window membrane via transtympanic injection.
- the pharmaceutical compositions described herein are administered directly onto the round window membrane via transtympanic injection.
- the pharmaceutical compositions described herein are administered onto the round window membrane via a non-transtympanic approach to the inner ear.
- the pharmaceutical composition described herein is administered onto the round window membrane via a surgical approach to the round window membrane comprising modification of the crista fenestrae cochleae.
- the delivery system is a syringe and needle apparatus that is capable of piercing the tympanic membrane and directly accessing the round window membrane or crista fenestrae cochleae of the auris interna.
- the delivery device is an apparatus designed for administration of therapeutic agents to the middle and/or inner ear.
- GYRUS Medical Gmbh offers micro-otoscopes for visualization of and drug delivery to the round window niche;
- Arenberg has described a medical treatment device to deliver fluids to inner ear structures in U.S. Pat. Nos. 5,421,818; 5,474,529; and 5,476,446.
- U.S. patent application Ser. No. 08/874,208 describes a surgical method for implanting a fluid transfer conduit to deliver therapeutic agents to the inner ear.
- U.S. Patent Application Publication 2007/0167918 further describes a combined otic aspirator and medication dispenser for intratympanic fluid sampling and medicament application.
- the pharmaceutical composition of the invention is useful in surgical procedures including, by way of non-limiting examples, cochlea surgery, labyrinthotomy, mastoidectomy, stapedectomy, endolymphatic sacculotomy or the like.
- the pharmaceutical composition as described herein is administered prior to surgical procedures in particular prior to cochlea surgery.
- the pharmaceutical composition described herein is administered for preventive and/or therapeutic treatments.
- Preventive treatments comprise prophylactic treatments.
- the pharmaceutical composition of the invention is administered to a subject suspected of having, or at risk for developing a disease, disorder or condition as described herein.
- the pharmaceutical composition of the invention is administered to a subject, such as a patient already suffering from a disorder disclosed herein, in an amount sufficient to cure or at least partially arrest the symptoms of the disease, disorder or condition as described herein. Amounts effective for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the subject's health status and response to the drugs, and the judgment of the treating physician.
- the pharmaceutical composition of the invention may be administered chronically, which is, for an extended period of time, including throughout the duration of the subject's life in order to ameliorate or otherwise control or limit the symptoms of the subject's disease or condition.
- the pharmaceutical composition of the invention may be given continuously; alternatively, the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a“drug holiday”).
- a maintenance dose of the pharmaceutical composition of the invention is administered, if necessary. Subsequently, the dosage or the frequency of administration, or both, is optionally reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained.
- the pharmaceutical composition of the invention is administered by a single injection into the inner ear and/or into the middle ear, preferably by a single intratympanic injection into the inner ear, followed by oral administration of a PPAR agonist or by a single intratympanic injection into the middle ear followed by oral
- a PPAR agonist which is preferred, or by administration of a PPAR agonist formulated as ear drops with penetration into the inner ear.
- Oral administration of a PPAR agonist can be provided chronically, which is, for an extended period of time, including throughout the duration of the subject's life.
- hearing capacity is increased based on a reactivation of hair cells from a resting state and/or improvement in neural cell function.
- hearing capacity is increased based on an increase of the number of hair cells or hair cell function or improved neural cell function subsequent to PPAR activation.
- the amount of the pharmaceutical composition of the invention to be administered will vary depending upon factors such as the disease condition and its severity, according to the particular circumstances surrounding the case, including, e.g., the specific PPAR agonist comprised by said pharmaceutical composition, the condition being treated, the target area being treated, and the subject or host being treated.
- the pharmaceutical composition of the invention comprises a PPAR agonist, usually a PPAR gamma agonist, PPAR alpha agonist and/or PPAR alpha/gamma dual agonist, preferably a PPAR gamma agonist, more preferably pioglitazone or a
- pharmaceutically acceptable salt thereof most preferably pioglitazone hydrochloride and is administered in human by injection into the inner ear and/or into the middle ear, preferably to the middle ear at a concentration of about 0.01% to about 7.5% w/v, preferably about 0.01% to about 5% w/v, more preferably about 0.1% to about 7.5% w/v, more preferably about 0.1% to about 5% w/v, more preferably about 0.1% to about 4% w/v, more preferably about 0.1% to about 3% w/v, more preferably about 0.1% to about 2% w/v, more preferably about 0.5% to about 2% w/v, more preferably about 0.5% to about 1.5% w/v, more preferably about 1% to about 1.5% w/v, most preferably about 1.2% w/v per single injection.
- Methods of identification of patients who are suspected of having, or being at risk for developing hearing loss, hair cell degeneration or hair cell death are also comprised by the present invention.
- patients who are suspected of having, or being at risk for developing hearing loss, hair cell degeneration or hair cell death are identified by measurement of serum and/or plasma adiponectin levels, in particular the measurement of high molecular weight adiponectin levels.
- the monitoring of the treatment success and/or the identification of the subject e.g. the identification of the subject who is suspected of having, or being at risk for developing hearing loss, hair cell degeneration or hair cell death, is achieved by measurement of serum and/or plasma adiponectin levels.
- kits generally will comprise the pharmaceutical composition disclosed herein, and instructions for using the kit.
- the disclosure also contemplates the use of the
- compositions disclosed herein in the manufacture of medicaments for treating, abating, reducing, or ameliorating the symptoms of a disease, dysfunction, or disorder in a mammal, such as a human that has, is suspected of having, or at risk for developing hearing loss, hair cell degeneration or hair cell death.
- kits include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) including one of the separate elements to be used in a method described herein.
- Suitable containers include, for example, bottles, vials, syringes, and test tubes.
- the containers are formed from a variety of materials such as glass or plastic.
- the articles of manufacture provided herein generally will comprise the pharmaceutical composition disclosed herein and packaging materials.
- pharmaceutical packaging materials include, but are not limited to, blister packs, tubes, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected composition and intended mode of administration and treatment. Examples
- Organs of Corti were obtained from post-natal day 5 Sprague-Dawley rats and placed in organ culture. Gentamicin treatment resulted is 50 - 70% loss of hair cells after 48h in culture. Pioglitazone co-treatment was protective, almost completely preventing gentamicin- dependent hair cell loss, and largely preserving organ morphology.
- OCs were harvested then placed in culture medium [Dulbecco’s Modified Eagle Medium supplemented with 10% FCS, 25 mM HEPES and 30 U/ml penicillin (Invitrogen, Carlsbad, CA, USA)] and incubated for 24 hours at 37°C in an atmosphere of 95% 02/5% C02. After that period, the culture medium was replaced with fresh medium containing no compound or 200mM gentamicin alone or 200 mM gentamicin with either 2 or 10 mM pioglitazone, and incubated for a further 48 hours at 37°C. Ten OC explants were used for each treatment condition.
- OCs were fixed in 4% paraformaldehyde, washed and then stained with a fluorescein (FITC)-conjugated phalloidin to detect inner and outer hair cells. After staining, the OCs were visualized and photographed using a fluorescence microscope (Olympus FSX100). Outer and inner hair cells were separately quantitated for the apical, basal, and middle turn of each organ of Corti. The values for each turn were averaged for the 10 OCs used for each condition. Significant differences between treatment groups in numbers OHC and IHC were determined using analysis of variance (ANOVA) followed by the least significant difference (LSD) post-hoc test (Stat View 5.0). Differences associated with P-values of less than 0.05 were considered to be statistically significant. All data are presented as mean ⁇ SD. Results
- Quantative image analysis was performed to count IHC and OHC separately in the apical, basal, and middle turns of each organ of Corti. While gentamicin treatment resulted in a consistent reduction of hair cell number of approximately 50 - 70% in each segment, pioglitazone at both concentrations was able to completely prevent gentamicin-dependent hair cell loss in all turns.
- a formulation of pioglitazone (composition according to Table 1 of Example 4) or vehicle alone was applied into the middle ears of guinea pigs.
- the animals were then exposed to a noise trauma (broadband noise 4 - 20 kHz, 115 dB (SPL) and recording of hearing sensitivity over the standard frequency range was performed 7-14 days later. Results obtained in the hearing test were compared to baseline values before injury. Pioglitazone protected hearing, resulting in a reduction of >50% in the threshold shifts in pioglitazone-treated animals vs. vehicle controls.
- the guinea pig model is the preferred animal species in hearing research.
- the agent application as well as the noise trauma was applied under general anesthesia.
- animals Upon arrival, animals underwent an acclimatization period of at least one week prior to experiments.
- Guinea pigs were first anaesthetized and hearing evaluated by a standard ABR method then into treatment groups. Each animal received a single round window application of test substance to both ears. The following day, animals were exposed to 115 dB broad band noise for 2 hrs under anaesthesia. At one and two weeks following noise exposure, the animals underwent a second hearing evaluation.
- ABR auditory brainstem responses
- the brainstem responses were amplified (IOO,OOOc), filtered (bandpass 0.15-3 kHz), and averaged (300x) by the Viking IV-system.
- the amplitudes of the ABR waves were measured at different sound intensities by changing the attenuation of signal amplification.
- the amplitude-growth function was calculated for each tested frequency, and a linear regression was fitted to the linear portion of the data.
- the hearing threshold could be calculated for each frequency by extrapolating the linear amplitude-grow function of the regression line to zero. From these data, threshold differences (mean threshold shifts) were calculated between the control and the noise-exposed animals using the average values. Results are represented as mean relative hearing loss ( ⁇ SD) in decibels (dB) of the experimental groups compared to controls.
- Vehicle treated animals showed a significant average hearing loss of 31.9 ⁇ 2.2 dB (mean ⁇ SD) over the frequency range of the noise challenge (5 - 20 kHz) at one week.
- Pioglitazone afforded significant protection of approximately 60 % from noise-induced hearing loss, with only modest threshold shifts of 12.7 ⁇ 1.3 dB (mean ⁇ SD) (Fig 2).
- PPARa-selective agonist fenofibric acid protected from gentamicin-dependent hair cell loss.
- Example 2 Methods were similar to those in Example 1. The main differences were that mouse OC’s were used rather than rat OC’s. Moreover, treatment was performed for 24 hrs with 50mM gentamicin. The number of OC’s used for each experimental condition was 3-5. The concentrations of test substances were 2 mM and 10 mM for tesaglitazar and muraglitazar, and 25 mM and 150 mM for fenofibric acid.
- Fenofibric acid was not effective at 25 mM but was completely protective at 150 mM (Fig 3 C).
- Example 4 Thermoreversible gel composition comprising pioglitazone hydrochloride Composition according to Table 1 :
- Trolamine is dissolved in water for injection; the solution is cooled to a temperature of not more than lO°C.
- Poloxamer 407 is added and dissolved by stirring
- packaging configuration as for instance, but not being limited to, vials, ampoules or pre-filled syringes
- Example 5 Suspension 1.2 % based on Poloxamer 407
- Example 6 Suspension 0.8 % based on Poloxamer 407 and Benzyl Alcohol as
- Tromethamine (TRIS) and Benzyl Alcohol are dissolved in water for injection; the solution is cooled to a temperature of not more than l0°C. Poloxamer 407 is added and dissolved by stirring
- packaging configuration as for instance, but not being limited to, vials, ampoules or pre-filled syringes
- Example 7 Suspension 1.0 % based on combination of Poloxamer 407 & Poloxamer 188
- Example 8 Suspension 0.5 % based on combination of Poloxamer & Hypromellose
- Hypromellose is dispersed in hot water for injection; under continuous stirring, the dispersion is cooled to room temperature to get into solution. Trolamine is dissolved in the resulting solution.
- Vitamin E Polyethylene Glycol Succinate is added and dissolved by stirring
- the sterile bulk product is filled into appropriate glass ampoules, which are closed by the well-known ampoule closing process based on a flame of mixed gas and oxygen to melt the glass.
- Example 10 Mucoadhesive Gel Suspension 1.0 % based on combination of Poloxamer & Carbomer (Carbopol®) Composition according to Table 7:
- Aqueous preparations which are prepared using aseptic precautions and which cannot be terminally sterilised may contain a suitable antimicrobial preservative in an appropriate concentration.
- this formulation is additionally not provided in a unit- dose container, it may contain a preservative
- Hypromellose, Methylparabene, and Propylparabene are dispersed in hot water for injection; under continuous stirring, the dispersion is cooled to room temperature to get into solution.
- Sodium Phosphate Monobasic Dihydrate (NaH2P04 2H20) is dissolved in the resulting solution.
- Example 11 Experimental Suspension 1.5 % based on PLGA-PEG- PLGA triblock copolymer
- packaging configuration e.g. vials.
- the material is frozen within the vials and stored at -20°C to guarantee appropriate chemical stability.
- thermoreversible gel composition according to Table 1 of Example 4
- NIHL noise-induced hearing loss
- mice were anesthetized and then placed in a sound-proof room and exposed for 60 min to a 120 dB 10 kHz sound to induce acute acoustic trauma and hearing loss.
- animals received pioglitazone 1.2% thermoreversible gel in right ears and corresponding vehicle in left ears by intra-tympanic injection (IT) under anesthesia.
- IT injections 30 m ⁇ were performed with a sterile motorized Hamilton 50-m1 syringe into the cochlear round window niche area at a constant rate (2 m ⁇ / s) .
- animals were treated in the same way but at 48 hr following the noise trauma.
- Hearing assessment 1 hr following sound exposure, animals received pioglitazone 1.2% thermoreversible gel in right ears and corresponding vehicle in left ears by intra-tympanic injection (IT) under anesthesia.
- IT injections 30 m ⁇ were performed with a sterile motorized Hamilton 50-m1 syringe into the cochlear round window
- ABR auditory brainstem responses
- a PC-controlled TDT System 3 (Tucker-Davis Technologies, Alachua, Florida, USA) data acquisition system with real time digital signal processing was used to record the ABR and to generate the auditory stimulus.
- the threshold value was defined as the lowest intensity able to evoke an appropriate ABR response.
- Hearing function was evaluated in all animals by measuring auditory brainstem responses (ABR) prior to noise exposure, and at multiple time points up to 21 days after noise exposure. The threshold values were the lowest intensity able to evoke an appropriate ABR response. Data are presented by frequency and represent the noise-induced threshold shift at the indicated time point vs. pre-noise exposure baseline levels.
- Example 4 The formulation of Example 4 (Table 1) was filled into 2.0 mL glass ampoules, stored at 5°C (r.H. not controlled) and 25°C/60% r.H, and thereafter tested on stability. The corresponding data are shown in Tables 9 and 10.
- Table 9 Stability Summary - Pioglitazone 1.2% Thermo-Reversible Suspension - 5°C (r.H. not controlled) Packaging Configuration: 2.0 ml Glass Ampoules
- Table 10 Stability Summary - Pioglitazone 1.2% Thermo-Reversible Suspension - 25°C / 60% r.H. Packaging Configuration: 2.0 ml Glass Ampoules
- TYL Turbid, whitish, suspension, liquid at ⁇ 25 °C, viscous gel at > 035°C
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Dermatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Organic Chemistry (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention concerne des compositions pharmaceutiques comprenant un agoniste de PPAR et un gel formulé pour la voie auriculaire, qui sont destinées à prévenir ou traiter la perte auditive et/ou à prévenir ou inhiber la dégénérescence ou la mort des cellules ciliées chez un sujet.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP18155840.4 | 2018-02-08 | ||
EP18155840 | 2018-02-08 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2019154895A1 true WO2019154895A1 (fr) | 2019-08-15 |
Family
ID=61188715
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2019/052971 WO2019154895A1 (fr) | 2018-02-08 | 2019-02-07 | Formulation en gel pour la prévention ou le traitement de la perte auditive |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2019154895A1 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10709732B2 (en) | 2018-02-09 | 2020-07-14 | Decibel Therapeutics, Inc. | Hypertonic pharmaceutical compositions containing an anti-platinum chemoprotectant agent |
US10813947B1 (en) | 2019-05-31 | 2020-10-27 | Decibel Therapeutics, Inc. | Methods of otoprotection against platinum-based antineoplastic agents |
Citations (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4687777A (en) | 1985-01-19 | 1987-08-18 | Takeda Chemical Industries, Ltd. | Thiazolidinedione derivatives, useful as antidiabetic agents |
US4900552A (en) | 1988-03-30 | 1990-02-13 | Watson Laboratories, Inc. | Mucoadhesive buccal dosage forms |
US4938763A (en) | 1988-10-03 | 1990-07-03 | Dunn Richard L | Biodegradable in-situ forming implants and methods of producing the same |
EP0551626A1 (fr) | 1991-12-19 | 1993-07-21 | LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d. | Gel thermoréversible utile comme excipient pharmaceutique pour une formation galénique |
US5324519A (en) | 1989-07-24 | 1994-06-28 | Atrix Laboratories, Inc. | Biodegradable polymer composition |
US5421818A (en) | 1993-10-18 | 1995-06-06 | Inner Ear Medical Delivery Systems, Inc. | Multi-functional inner ear treatment and diagnostic system |
US5702716A (en) | 1988-10-03 | 1997-12-30 | Atrix Laboratories, Inc. | Polymeric compositions useful as controlled release implants |
US5744153A (en) | 1994-04-08 | 1998-04-28 | Atrix Laboratories, Inc. | Liquid delivery compositions |
US5814330A (en) | 1994-05-18 | 1998-09-29 | Janssen Pharmaceutica, N.V. | Mucoadhesive emulsions containing cyclodextrin |
US6004573A (en) | 1997-10-03 | 1999-12-21 | Macromed, Inc. | Biodegradable low molecular weight triblock poly(lactide-co-glycolide) polyethylene glycol copolymers having reverse thermal gelation properties |
US6117949A (en) | 1998-10-01 | 2000-09-12 | Macromed, Inc. | Biodegradable low molecular weight triblock poly (lactide-co-glycolide) polyethylene glycol copolymers having reverse thermal gelation properties |
US6201072B1 (en) | 1997-10-03 | 2001-03-13 | Macromed, Inc. | Biodegradable low molecular weight triblock poly(lactide-co- glycolide) polyethylene glycol copolymers having reverse thermal gelation properties |
US6287588B1 (en) | 1999-04-29 | 2001-09-11 | Macromed, Inc. | Agent delivering system comprised of microparticle and biodegradable gel with an improved releasing profile and methods of use thereof |
US6306789B1 (en) | 1995-03-13 | 2001-10-23 | Reckitt Benckiser Healthcare (Uk) Limited | Mucoadhesive granules of carbomer suitable for oral administration of drugs |
US6319513B1 (en) | 1998-08-24 | 2001-11-20 | The Procter & Gamble Company | Oral liquid mucoadhesive compounds |
US6348502B1 (en) | 1998-06-10 | 2002-02-19 | Reckitt & Colman Products Limited | Formulations for the treatment of gastro-oesophageal reflux |
US6509028B2 (en) | 2000-06-26 | 2003-01-21 | Epicept Corporation | Methods and compositions for treating pain of the mucous membrane |
US6562363B1 (en) | 1997-09-26 | 2003-05-13 | Noven Pharmaceuticals, Inc. | Bioadhesive compositions and methods for topical administration of active agents |
US6638521B2 (en) | 1998-08-24 | 2003-10-28 | The Procter & Gamble Company | Oral liquid mucoadhesive compositions |
US20070167918A1 (en) | 2004-05-24 | 2007-07-19 | Auris Medical Llc | Combined otic aspirator and medication dispenser |
US20100016450A1 (en) * | 2008-07-21 | 2010-01-21 | Otonomy, Inc. | Controlled release delivery devices for the treatment of otic disorders |
GB2461961A (en) * | 2008-07-14 | 2010-01-27 | Otonomy Inc | Sterile anti-apoptotic agent for treatment of ear diseases |
WO2016066666A1 (fr) * | 2014-10-30 | 2016-05-06 | Sanovel Ilac Sanayi Ve Ticaret A.S. | Combinaisons pharmaceutiques de sitagliptine et d'agonistes de ppar |
WO2016128438A1 (fr) * | 2015-02-11 | 2016-08-18 | Support-Venture Gmbh | Méthode de prévention ou de traitement de la perte audititive |
-
2019
- 2019-02-07 WO PCT/EP2019/052971 patent/WO2019154895A1/fr active Application Filing
Patent Citations (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4687777A (en) | 1985-01-19 | 1987-08-18 | Takeda Chemical Industries, Ltd. | Thiazolidinedione derivatives, useful as antidiabetic agents |
US4900552A (en) | 1988-03-30 | 1990-02-13 | Watson Laboratories, Inc. | Mucoadhesive buccal dosage forms |
US5702716A (en) | 1988-10-03 | 1997-12-30 | Atrix Laboratories, Inc. | Polymeric compositions useful as controlled release implants |
US4938763B1 (en) | 1988-10-03 | 1995-07-04 | Atrix Lab Inc | Biodegradable in-situ forming implants and method of producing the same |
US5990194A (en) | 1988-10-03 | 1999-11-23 | Atrix Laboratories, Inc. | Biodegradable in-situ forming implants and methods of producing the same |
US4938763A (en) | 1988-10-03 | 1990-07-03 | Dunn Richard L | Biodegradable in-situ forming implants and methods of producing the same |
US5324519A (en) | 1989-07-24 | 1994-06-28 | Atrix Laboratories, Inc. | Biodegradable polymer composition |
EP0551626A1 (fr) | 1991-12-19 | 1993-07-21 | LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d. | Gel thermoréversible utile comme excipient pharmaceutique pour une formation galénique |
US5421818A (en) | 1993-10-18 | 1995-06-06 | Inner Ear Medical Delivery Systems, Inc. | Multi-functional inner ear treatment and diagnostic system |
US5474529A (en) | 1993-10-18 | 1995-12-12 | Inner Ear Medical Delivery Systems, Inc. | Multi-functional inner ear treatment and diagnostic system |
US5476446A (en) | 1993-10-18 | 1995-12-19 | Inner Ear Medical Delivery Systems, Inc. | Multi-functional inner ear treatment and diagnostic system |
US5744153A (en) | 1994-04-08 | 1998-04-28 | Atrix Laboratories, Inc. | Liquid delivery compositions |
US5814330A (en) | 1994-05-18 | 1998-09-29 | Janssen Pharmaceutica, N.V. | Mucoadhesive emulsions containing cyclodextrin |
US6306789B1 (en) | 1995-03-13 | 2001-10-23 | Reckitt Benckiser Healthcare (Uk) Limited | Mucoadhesive granules of carbomer suitable for oral administration of drugs |
US6562363B1 (en) | 1997-09-26 | 2003-05-13 | Noven Pharmaceuticals, Inc. | Bioadhesive compositions and methods for topical administration of active agents |
US6201072B1 (en) | 1997-10-03 | 2001-03-13 | Macromed, Inc. | Biodegradable low molecular weight triblock poly(lactide-co- glycolide) polyethylene glycol copolymers having reverse thermal gelation properties |
US6004573A (en) | 1997-10-03 | 1999-12-21 | Macromed, Inc. | Biodegradable low molecular weight triblock poly(lactide-co-glycolide) polyethylene glycol copolymers having reverse thermal gelation properties |
US6348502B1 (en) | 1998-06-10 | 2002-02-19 | Reckitt & Colman Products Limited | Formulations for the treatment of gastro-oesophageal reflux |
US6319513B1 (en) | 1998-08-24 | 2001-11-20 | The Procter & Gamble Company | Oral liquid mucoadhesive compounds |
US6638521B2 (en) | 1998-08-24 | 2003-10-28 | The Procter & Gamble Company | Oral liquid mucoadhesive compositions |
US6117949A (en) | 1998-10-01 | 2000-09-12 | Macromed, Inc. | Biodegradable low molecular weight triblock poly (lactide-co-glycolide) polyethylene glycol copolymers having reverse thermal gelation properties |
US6287588B1 (en) | 1999-04-29 | 2001-09-11 | Macromed, Inc. | Agent delivering system comprised of microparticle and biodegradable gel with an improved releasing profile and methods of use thereof |
US6509028B2 (en) | 2000-06-26 | 2003-01-21 | Epicept Corporation | Methods and compositions for treating pain of the mucous membrane |
US20070167918A1 (en) | 2004-05-24 | 2007-07-19 | Auris Medical Llc | Combined otic aspirator and medication dispenser |
GB2461961A (en) * | 2008-07-14 | 2010-01-27 | Otonomy Inc | Sterile anti-apoptotic agent for treatment of ear diseases |
US20100016450A1 (en) * | 2008-07-21 | 2010-01-21 | Otonomy, Inc. | Controlled release delivery devices for the treatment of otic disorders |
WO2016066666A1 (fr) * | 2014-10-30 | 2016-05-06 | Sanovel Ilac Sanayi Ve Ticaret A.S. | Combinaisons pharmaceutiques de sitagliptine et d'agonistes de ppar |
WO2016128438A1 (fr) * | 2015-02-11 | 2016-08-18 | Support-Venture Gmbh | Méthode de prévention ou de traitement de la perte audititive |
Non-Patent Citations (23)
Title |
---|
ADABAG AS; MITHANI S; A1 ALOUL B; COLLINS D; BERTOG S; BLOOMFIELD HE: "Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group", AM HEART J., vol. 157, no. 5, May 2009 (2009-05-01), pages 913 - 8 |
AGRAWAL R, CURR DRUG TARGETS, vol. 15, no. 2, February 2014 (2014-02-01), pages 151 - 5 |
AHLAWAT P; SRINIVAS NR, EUR J DRUG METAB PHARMACOKINET., vol. 33, no. 3, July 2008 (2008-07-01), pages 187 - 90 |
BARRENAS ML; JONSSON B; TUVEMO T; HELLSTROM PA; LUNDGREN M, J CLIN ENDOCRINOL METAB., vol. 90, no. 8, 31 May 2005 (2005-05-31), pages 4452 - 6 |
BAYS H; MCELHATTAN J; BRYZINSKI BS: "GALLANT 6 Study Group", DIAB VASC DIS RES., vol. 4, no. 3, September 2007 (2007-09-01), pages 181 - 93 |
BONDS DE; CRAVEN TE; BUSE J; CROUSE JR; CUDDIHY R; ELAM M; GINSBERG HN; KIRCHNER K; MARCOVINA S; MYCHALECKYJ JC, DIABETOLOGIA, vol. 55, no. 6, June 2012 (2012-06-01), pages 1641 - 50 |
C. M. SUE: "PhD, FRACP1, Cochlear origin of hearing loss in MELAS syndrome", ANNALS OF NEUROLOGY, vol. 43, no. 3, March 1998 (1998-03-01), pages 350 - 359 |
CARIOU B; STAELS B, EXPERT OPIN INVESTIG DRUGS, vol. 23, no. 10, October 2014 (2014-10-01), pages 1441 - 8 |
DORMANDY JA; CHARBONNEL B; ECKLAND DJ; ERDMANN E; MASSI-BENEDETTI M; MOULES IK; SKENE AM; TAN MH; LEFEBVRE PJ; MURRAY GD: "PROactive investigators", LANCET, vol. 366, no. 9493, 8 October 2005 (2005-10-08), pages 1279 - 89 |
FERNANDEZ M; GASTALDELLI A; TRIPLITT C; HARDIES J; CASOLARO A; PETZ R; TANTIWONG P; MUSI N; CERSOSIMO E; FERRANNINI E, DIABETES OBES METAB., vol. 13, no. 10, October 2011 (2011-10-01), pages 893 - 902 |
FLOREZ JC; JABLONSKI KA; SUN MW; BAYLEY N; KAHN SE; SHAMOON H; HAMMAN RF; KNOWLER WC; NATHAN DM; ALTSHULER D: "Diabetes Prevention Program Research Group", J CLIN ENDOCRINOL METAB., vol. 92, no. 4, April 2007 (2007-04-01), pages 1502 - 9 |
JEONG ET AL., ADV. DRUG DELIVERY REV., vol. 54, 2002, pages 37 - 51 |
JEONG ET AL., J. CONTROL. RELEASE, vol. 63, 2000, pages 155 - 63 |
LINCOFF AM; TARDIF JC; SCHWARTZ GG; NICHOLLS SJ; RYDEN L; NEAL B; MALMBERG K; WEDEL H; BUSE JB; HENRY RR: "AleCardio Investigators", JAMA, vol. 311, no. 15, 16 April 2014 (2014-04-16), pages 1515 - 25 |
MAJITHIYA ET AL., AAPS PHARMSCITECH, vol. 7, no. 3, 2006 |
N ENGL J MED., vol. 357, no. 1, 5 July 2007 (2007-07-05), pages 100 |
NISSEN SE; WOLSKI K, N ENGL J MED., vol. 356, no. 24, 14 June 2007 (2007-06-14), pages 2457 - 71 |
RABKIN SW; HAYDEN M; FROHLICH J, ATHEROSCLEROSIS, vol. 73, no. 2-3, October 1988 (1988-10-01), pages 233 - 40 |
SAAD MF; GRECO S; OSEI K; LEWIN AJ; EDWARDS C; NUNEZ M; REINHARDT RR: "Ragaglitazar Dose-Ranging Study Group", DIABETES CARE, vol. 27, no. 6, June 2004 (2004-06-01), pages 1324 - 9 |
SCHIMA SM; MACIEJEWSKI SR; HILLEMAN DE; WILLIAMS MA; MOHIUDDIN SM, EXPERT OPIN PHARMACOTHER, vol. 11, no. 5, April 2010 (2010-04-01), pages 731 - 8 |
SOBKOWICZ HM; LOFTUS JM; SLAPNICK SM, ACTA OTOLARYNGOL, vol. 502, 1993, pages 3 - 36 |
TAYGERLY JP; MCGEE LR; RUBENSTEIN SM; HOUZE JB; CUSHING TD; LI Y; MOTANI A; CHEN JL; FRANKMOELLE W; YE G, BIOORG MED CHEM., vol. 21, no. 4, 15 February 2013 (2013-02-15), pages 979 - 92 |
WANG X; SNG MK; FOO S; CHONG HC; LEE WL; TANG MB; NG KW; LUO B; CHOONG C; WONG MT, J CONTROL RELEASE, vol. 197, 10 January 2015 (2015-01-10), pages 138 - 47 |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10709732B2 (en) | 2018-02-09 | 2020-07-14 | Decibel Therapeutics, Inc. | Hypertonic pharmaceutical compositions containing an anti-platinum chemoprotectant agent |
US11071751B2 (en) | 2018-02-09 | 2021-07-27 | Decibel Therapeutics, Inc. | Hypertonic pharmaceutical compositions containing an anti-platinum chemoprotectant agent |
US11857567B2 (en) | 2018-02-09 | 2024-01-02 | Decibel Therapeutics, Inc. | Hypertonic pharmaceutical compositions containing an anti-platinum chemoprotectant agent |
US10813947B1 (en) | 2019-05-31 | 2020-10-27 | Decibel Therapeutics, Inc. | Methods of otoprotection against platinum-based antineoplastic agents |
US11690870B2 (en) | 2019-05-31 | 2023-07-04 | Decibel Therapeutics, Inc. | Methods of otoprotection against platinum-based antineoplastic agents |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2723458C (fr) | Compositions de corticosteroides a liberation controlee et procedes pour le traitement de troubles otiques | |
US20180021320A1 (en) | Method of Preventing or Treating Hearing Loss | |
WO2015031393A1 (fr) | Méthodes pour le traitement de troubles otiques chez les enfants | |
WO2019154895A1 (fr) | Formulation en gel pour la prévention ou le traitement de la perte auditive | |
WO2025040177A1 (fr) | Composition lyophilisée de phosphate sodique de dexaméthasone appropriée pour une administration à la membrane tympanique et son procédé de préparation | |
CN111773187B (zh) | 一种地塞米松磷酸钠冻干粉针剂 | |
TWI382839B (zh) | 控制釋放之皮質類固醇組成物及其用於耳部失調治療的方法 | |
HK1191867B (en) | Controlled release corticosteroid compositions and methods for the treatment of otic disorders | |
HK1191867A (en) | Controlled release corticosteroid compositions and methods for the treatment of otic disorders | |
HK1156533B (en) | Controlled release corticosteroid compositions and methods for the treatment of otic disorders |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 19702465 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 19702465 Country of ref document: EP Kind code of ref document: A1 |