EP1139970A2 - The process for manufacturing topical ophthalmic preparations without systemic effects - Google Patents
The process for manufacturing topical ophthalmic preparations without systemic effectsInfo
- Publication number
- EP1139970A2 EP1139970A2 EP00925571A EP00925571A EP1139970A2 EP 1139970 A2 EP1139970 A2 EP 1139970A2 EP 00925571 A EP00925571 A EP 00925571A EP 00925571 A EP00925571 A EP 00925571A EP 1139970 A2 EP1139970 A2 EP 1139970A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- polymer
- timolol
- drug
- formulation
- carbopol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 230000000699 topical effect Effects 0.000 title claims abstract description 33
- 230000009885 systemic effect Effects 0.000 title claims abstract description 32
- 238000000034 method Methods 0.000 title claims abstract description 21
- 230000008569 process Effects 0.000 title claims abstract description 18
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 8
- 238000002360 preparation method Methods 0.000 title claims description 31
- 229920000642 polymer Polymers 0.000 claims abstract description 21
- 229920002125 Sokalan® Polymers 0.000 claims abstract description 16
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims abstract description 3
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims abstract description 3
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims abstract description 3
- 230000003232 mucoadhesive effect Effects 0.000 claims abstract description 3
- 229940079593 drug Drugs 0.000 claims description 32
- 239000003814 drug Substances 0.000 claims description 32
- 238000009472 formulation Methods 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 7
- 239000004584 polyacrylic acid Substances 0.000 claims description 7
- 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 claims description 6
- 229920000148 Polycarbophil calcium Polymers 0.000 claims description 6
- 229940075510 carbopol 981 Drugs 0.000 claims description 6
- 229950005134 polycarbophil Drugs 0.000 claims description 6
- 239000000872 buffer Substances 0.000 claims description 3
- 239000012669 liquid formulation Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 239000003755 preservative agent Substances 0.000 claims description 3
- 229920002907 Guar gum Polymers 0.000 claims description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 239000013020 final formulation Substances 0.000 claims description 2
- 239000000665 guar gum Substances 0.000 claims description 2
- 229960002154 guar gum Drugs 0.000 claims description 2
- 235000010417 guar gum Nutrition 0.000 claims description 2
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 229940068984 polyvinyl alcohol Drugs 0.000 claims description 2
- 229920001285 xanthan gum Polymers 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims 1
- 239000007900 aqueous suspension Substances 0.000 claims 1
- 229960001631 carbomer Drugs 0.000 claims 1
- 239000000839 emulsion Substances 0.000 claims 1
- 238000012856 packing Methods 0.000 claims 1
- 229920001290 polyvinyl ester Polymers 0.000 claims 1
- 238000003756 stirring Methods 0.000 claims 1
- 230000002708 enhancing effect Effects 0.000 abstract 1
- 229920003023 plastic Polymers 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 30
- 229960004605 timolol Drugs 0.000 description 30
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 23
- 229960002896 clonidine Drugs 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 20
- 239000008215 water for injection Substances 0.000 description 20
- CHDPSNLJFOQTRK-UHFFFAOYSA-N betaxolol hydrochloride Chemical compound [Cl-].C1=CC(OCC(O)C[NH2+]C(C)C)=CC=C1CCOCC1CC1 CHDPSNLJFOQTRK-UHFFFAOYSA-N 0.000 description 17
- 229960004324 betaxolol Drugs 0.000 description 13
- WLRMANUAADYWEA-NWASOUNVSA-N (S)-timolol maleate Chemical compound OC(=O)\C=C/C(O)=O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 WLRMANUAADYWEA-NWASOUNVSA-N 0.000 description 12
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 12
- 229960005221 timolol maleate Drugs 0.000 description 9
- ZNIFSRGNXRYGHF-UHFFFAOYSA-N Clonidine hydrochloride Chemical compound Cl.ClC1=CC=CC(Cl)=C1NC1=NCCN1 ZNIFSRGNXRYGHF-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 229960002925 clonidine hydrochloride Drugs 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 230000036470 plasma concentration Effects 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 229940068196 placebo Drugs 0.000 description 6
- 239000000902 placebo Substances 0.000 description 6
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 4
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 4
- 239000002876 beta blocker Substances 0.000 description 4
- 229940097320 beta blocking agent Drugs 0.000 description 4
- 229960004347 betaxolol hydrochloride Drugs 0.000 description 4
- 229940061607 dibasic sodium phosphate Drugs 0.000 description 4
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 4
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 4
- 239000006196 drop Substances 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 229960001802 phenylephrine Drugs 0.000 description 4
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 3
- 239000003889 eye drop Substances 0.000 description 3
- 229940012356 eye drops Drugs 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 210000002850 nasal mucosa Anatomy 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- XYLJNLCSTIOKRM-UHFFFAOYSA-N Alphagan Chemical compound C1=CC2=NC=CN=C2C(Br)=C1NC1=NCCN1 XYLJNLCSTIOKRM-UHFFFAOYSA-N 0.000 description 2
- 229930003347 Atropine Natural products 0.000 description 2
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 2
- -1 Loteprednol Ebanoate Chemical compound 0.000 description 2
- 206010047571 Visual impairment Diseases 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 229960002610 apraclonidine Drugs 0.000 description 2
- IEJXVRYNEISIKR-UHFFFAOYSA-N apraclonidine Chemical compound ClC1=CC(N)=CC(Cl)=C1NC1=NCCN1 IEJXVRYNEISIKR-UHFFFAOYSA-N 0.000 description 2
- 229960000396 atropine Drugs 0.000 description 2
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 2
- 229960003679 brimonidine Drugs 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 210000000795 conjunctiva Anatomy 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- IXHBTMCLRNMKHZ-LBPRGKRZSA-N levobunolol Chemical compound O=C1CCCC2=C1C=CC=C2OC[C@@H](O)CNC(C)(C)C IXHBTMCLRNMKHZ-LBPRGKRZSA-N 0.000 description 2
- 229960000831 levobunolol Drugs 0.000 description 2
- 230000002911 mydriatic effect Effects 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 230000000284 resting effect Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 1
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 1
- 206010000087 Abdominal pain upper Diseases 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- IECPWNUMDGFDKC-UHFFFAOYSA-N Fusicsaeure Natural products C12C(O)CC3C(=C(CCC=C(C)C)C(O)=O)C(OC(C)=O)CC3(C)C1(C)CCC1C2(C)CCC(O)C1C IECPWNUMDGFDKC-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 206010039424 Salivary hypersecretion Diseases 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- BGDKAVGWHJFAGW-UHFFFAOYSA-N Tropicamide Chemical compound C=1C=CC=CC=1C(CO)C(=O)N(CC)CC1=CC=NC=C1 BGDKAVGWHJFAGW-UHFFFAOYSA-N 0.000 description 1
- 206010046555 Urinary retention Diseases 0.000 description 1
- 206010047513 Vision blurred Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000036471 bradycardia Effects 0.000 description 1
- 208000006218 bradycardia Diseases 0.000 description 1
- 230000002612 cardiopulmonary effect Effects 0.000 description 1
- 229960001222 carteolol Drugs 0.000 description 1
- LWAFSWPYPHEXKX-UHFFFAOYSA-N carteolol Chemical compound N1C(=O)CCC2=C1C=CC=C2OCC(O)CNC(C)(C)C LWAFSWPYPHEXKX-UHFFFAOYSA-N 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 229960001815 cyclopentolate Drugs 0.000 description 1
- SKYSRIRYMSLOIN-UHFFFAOYSA-N cyclopentolate Chemical compound C1CCCC1(O)C(C(=O)OCCN(C)C)C1=CC=CC=C1 SKYSRIRYMSLOIN-UHFFFAOYSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 230000035487 diastolic blood pressure Effects 0.000 description 1
- 230000003205 diastolic effect Effects 0.000 description 1
- 206010013781 dry mouth Diseases 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 229960003704 framycetin Drugs 0.000 description 1
- PGBHMTALBVVCIT-VCIWKGPPSA-N framycetin Chemical compound N[C@@H]1[C@@H](O)[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[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CN)O2)N)O[C@@H]1CO PGBHMTALBVVCIT-VCIWKGPPSA-N 0.000 description 1
- 229940048400 fucidin Drugs 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960001798 loteprednol Drugs 0.000 description 1
- YPZVAYHNBBHPTO-MXRBDKCISA-N loteprednol Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)OCCl)[C@@H]4[C@@H]3CCC2=C1 YPZVAYHNBBHPTO-MXRBDKCISA-N 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 229960002704 metipranolol Drugs 0.000 description 1
- BQIPXWYNLPYNHW-UHFFFAOYSA-N metipranolol Chemical compound CC(C)NCC(O)COC1=CC(C)=C(OC(C)=O)C(C)=C1C BQIPXWYNLPYNHW-UHFFFAOYSA-N 0.000 description 1
- 230000003547 miosis Effects 0.000 description 1
- 239000003604 miotic agent Substances 0.000 description 1
- 239000002637 mydriatic agent Substances 0.000 description 1
- 210000004083 nasolacrimal duct Anatomy 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 1
- 229960001180 norfloxacin Drugs 0.000 description 1
- 229960001699 ofloxacin Drugs 0.000 description 1
- 208000035824 paresthesia Diseases 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- HJHVQCXHVMGZNC-JCJNLNMISA-M sodium;(2z)-2-[(3r,4s,5s,8s,9s,10s,11r,13r,14s,16s)-16-acetyloxy-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-methylhept-5-enoate Chemical compound [Na+].O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C([O-])=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C HJHVQCXHVMGZNC-JCJNLNMISA-M 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 208000037905 systemic hypertension Diseases 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 238000012360 testing method Methods 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
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- 229960004791 tropicamide Drugs 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 230000002618 waking effect Effects 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
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- 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
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
Definitions
- the present invention relates to the process for manufacturing topical ophthalmic preparations without systemic effects.
- Many topical ophthalmic preparations have- systemic effects. These systemic effects are responsible for contraindications, side effects, toxicity of some of the topical ophthalmic preparations. Similarly, due to systemic effects certain topical ophthalmic preparations have not been commercialized.
- the present invention is directed to manufacturing topical ophthalmic preparations in such a way that systemic effects of that topical ophthalmic preparation do not manifest.
- Topical ophthalmic preparations can be divided into two groups.
- One of the group includes preparations in which active ingredients are for topical use only and have no systemic effects.
- These group of drugs include antibiotics like Framycetin, Neomycin, Fucidin, steroids like Loteprednol Ebanoate, Triamcinolone, alpha agonist like Apraclonidine, Brimonidine, etc.
- the other group of topical ophthalmic preparations have active ingredients which are generally used for their effects.
- These group of preparations include antibiotics like Ciprofloxacin, Norfloxacin, Ofloxacin, Gentamicin, Tobramycin, steroids like Dexamethasone, Betamethasone, ⁇ -blockers like Timolol, Betaxolol, etc.
- systemic effects When used topically are also found to have systemic effects. When systemic effects are serious in nature, it results in limiting the use of a drug in the form of contraindication or amount of drug to be used.
- systemic effects of topical ophthalmic preparations include cardiopulmonary effects of ⁇ -blockers like Timolol, Levobunolol, Metipranolol, Carteolol, etc. Dryness of mouth, flush, fever, tachycardia, urinary retention, convulsion irritability are found with Atropine eye drops. Systemic hypertension is associated with topical mydriatic phenylephrine.
- Systemic effects are due to plasma concentration of a drug. It depends on absorption of the drug from conjunctiva or nasal mucosa into systemic circulation (serum levels of drug).
- the mechanisms to reduce plasma concentration of a drug includes reduction in drop size. It reduces the amount of drug available through conjunctiva as well as nasal mucosa.
- the blockage of nasolacrimal duct temporarily or permanently also reduces drug reaching to nasal mucosa through nasolacrimal passages and thus reduces the amount of drug available systemically.
- Increasing the viscosity of a formulation also reduces the plasma concentration of a drug.
- Slow release of a drug through sustained release mechanism/device are known to reduce plasma concentration of topical ophthalmic preparations. Including vasoconstrictive agents into a topical ophthalmic preparation also reduces the plasma level of topically applied drugs.
- the other mechanism used to reduce systemic effects include use of a prodrug as topical ophthalmic preparation which gets converted to active compound only at the site of action, e.g. Dipivetrin for epinephrine and Phenylephrine Oxazoline for Phenylephrine.
- the other mechanism known includes formulating a preparation as an ointment.
- the tear film formed with the use of ointment is thick, with poor light transmission and irregular anterior surface. This results in blurring of vision and so have not been popular. It also causes stickiness of lashes and lid margin. This limits its use to a great extent and whenever used, its use is restricted for bed time application.
- Aqueous vs viscous phenylephrine Aqueous vs viscous phenylephrine. I. Systemic absorption and cardiovascular effects.
- the objective of present invention is to provide topical ophthalmic preparations without systemic effects without reducing the concentration of active ingredient.
- the further objective of present invention is to provide topical ophthalmic preparations which does not cause significant visual disturbances to limit its use during waking hours.
- the further objective of present invention is to provide topical ophthalmic preparations which are equally effective after longer period of storage.
- the further objective of present invention is to provide topical ophthalmic preparations which do not require special storage conditions.
- Liquid formulation of a selected drug is prepared which contains excipients buffers and preservatives in distilled water. The pH of this solution is adjusted to provide stable formulation for topical ophthalmic use.
- polymer is dissolved into a solvent preferably water and stirred well till gel is formed.
- Solution containing selected drug as formulated in step 1 is gradually added to the gel as formed in step 2.
- Volume is made up by adding distilled water/solvent as required.
- pH is checked and adjusted as necessary to provide stable formulation for topical instillation into eye.
- the drug described above can be any of the existing ophthalmic preparations or any other drug which cannot be used as a topical preparation in a desired concentration for instillation into eye.
- the drugs which are most frequently used and are known to have systemic effects include ⁇ -blockers like Timolol, Levobunolol, Metipranalol, etc.
- mydriatics like phenylephrine, atropine, cyclopentolate, tropicamide have systemic effects and their use is restricted by it.
- Clonidine is an example of a drug which lowers I.O.P. significantly but cannot be used as 0.1% or 0.2% concentration due to its systemic hypotensive effect.
- the polymer to be used for preparing topical formulation as per present invention should form a gel when solubilized.
- polymer selected demonstrates pseudoplastic behaviour in a formulation.
- Polymer to be used for the purpose of present invention having above properties are known and includes polyacrylic acid, polyacrylic esters, polycarbophile, polyvinyl Acetate, Acrypol, Xantham gum, Guar gum, hydroxy ethyl cellulose, polyvinyl alcohol, PVP, carbomers, hydrogels prepared by combination of various polymers etc. Names of above polymer exemplifies the process and are not restricted to for the purpose of invention.
- viscosity For the purpose of avoiding systemic effects of a formulation prepared as per present invention, it is necessary to have viscosity above 100,000 cps (one hundred thousand cps), preferably above 400,000 (four hundred thousand cps).
- the final volume adjustment and amount of polymer to be used has to be designed considering these requirements.
- the amount of polymer in a final formulation to get desired viscosity is variable but is well known. It varies with polymer to polymer and also with molecular weight of some polymer.
- compositions so manufactured can be sterilized by known methods of sterilizing, including autoclaving. If sterilization process is likely to result in unstabilization of drug, it can be prepared as a sterile product throughout the process.
- Carbopol ETD 2001 1.5 gm to 2.5 gm Sodium hydroxide to adjust pH 6.5 to 7.5
- Clonidine hydrochloride 0.1 gm Benzylconium chloride 0.0107 gm Polyacrylic Acid 1.5 gm to 2.5 gm
- Carbopol ETD 2001 1.5 gm to 2.5 gm Sodium hydroxide to adjust pH 6.5 to 7.5
- Carbopol ETD 2001 1.5 gm to 2.5 gm Sodium hydroxide to adjust pH 6.5 to 7.5
- Carbopol 981 1.5 gm to 2.5 gm Sodium hydroxide to adjust pH 6.5 to 7.5
- Carbopol 981 1.5 gm to 2.5 gm Sodium hydroxide to adjust pH 6.5 to 7.5
- Betaxolol hydrochloride 0.56 gm. equivalent to 0.5 gm of Betaxolol
- Betaxolol hydrochloride 0.56 gm. equivalent to 0.5 gm of Betaxolol
- Betaxolol hydrochloride 0.56 gm. equivalent to 0.5 gm of Betaxolol
- Betaxolol hydrochloride 0.56 gm. equivalent to 0.5 gm of Betaxolol
- composition so manufactured is evaluated at different test conditions of temperature and humidity (as per ICH guidelines, 40°C/75% RH, 25°C/60% RH) for time interval extending upto 12 months.
- the topical ophthalmic preparation of Timolol Maleate 0.5% made according to present invention was evaluated for systemic effects and compared with Timolol eye drops and Timoptic XE.
- present invention provides process for manufacturing of topical ophthalmic preparations without systemic effects.
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Ophthalmology & Optometry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN90BO1999 IN185228B (enrdf_load_stackoverflow) | 1999-02-03 | 1999-02-03 | |
| INBO009099 | 1999-02-03 | ||
| PCT/IN2000/000008 WO2000049990A2 (en) | 1999-02-03 | 2000-02-02 | The process for manufacturing topical ophthalmic preparations without systemic effects |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1139970A2 true EP1139970A2 (en) | 2001-10-10 |
Family
ID=11077485
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP00925571A Withdrawn EP1139970A2 (en) | 1999-02-03 | 2000-02-02 | The process for manufacturing topical ophthalmic preparations without systemic effects |
Country Status (11)
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8858961B2 (en) | 2000-07-14 | 2014-10-14 | Allergan, Inc. | Compositions containing alpha-2-adrenergic agonist components |
| BR0109317A (pt) * | 2000-07-14 | 2003-06-17 | Allergan Inc | Composições contendo componentes agonistas alfa-2-adrenérgicos |
| AU2005220199B2 (en) * | 2000-07-14 | 2007-03-08 | Allergan, Inc. | Compositions containing alpha-2-adrenergic agonist components |
| DE10132876A1 (de) * | 2001-07-06 | 2003-01-30 | Medproject Pharma Entwicklungs | Zweiphasige, tropfbare Hydrogele zur Anwendung am Auge |
| US7439241B2 (en) | 2003-05-27 | 2008-10-21 | Galderma Laboratories, Inc. | Compounds, formulations, and methods for treating or preventing rosacea |
| ES2424644T3 (es) | 2004-05-25 | 2013-10-07 | Galderma Pharma S.A. | Compuestos, formulaciones y métodos para tratar o prevenir los trastornos inflamatorios de la piel |
| EP2329849B1 (en) | 2009-11-18 | 2015-04-29 | Galderma Research & Development | Combination of alpha-2 adrenergic receptor agonist and non-steroidal anti-inflammatory agent for treating or preventing an inflammatory skin disorder |
| FR2977493B1 (fr) | 2011-07-05 | 2014-02-14 | Galderma Res & Dev | Nouvelle composition anesthesique stable pour la reduction des reactions cutanees |
| RU2641021C2 (ru) | 2013-02-15 | 2018-01-17 | Аллерган, Инк. | Имплантат для пролонгированной доставки лекарственного средства |
| WO2014150899A1 (en) * | 2013-03-15 | 2014-09-25 | Chapin Matthew J | Topical ophthalmic formulations for treating migraine |
| US9421199B2 (en) | 2014-06-24 | 2016-08-23 | Sydnexis, Inc. | Ophthalmic composition |
| WO2016172712A2 (en) | 2015-04-23 | 2016-10-27 | Sydnexis, Inc. | Ophthalmic composition |
| US11382909B2 (en) | 2014-09-05 | 2022-07-12 | Sydnexis, Inc. | Ophthalmic composition |
| HK1248570A1 (zh) | 2015-05-29 | 2018-10-19 | 西德奈克西斯公司 | D2o稳定化的药物制剂 |
| GB202110420D0 (en) * | 2021-07-20 | 2021-09-01 | Rosemont Pharmaceuticals Ltd | Liquid pharmaceutical composition of clonidine |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2007091A (en) * | 1977-11-07 | 1979-05-16 | Toko Yakuhin Kogyo Kk | Ophthalmic composition |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DD294174A5 (de) * | 1990-05-04 | 1991-09-26 | Sigrid Keipert | Ophthalmika mit retardwirkung und ein neues verfahren zu ihrer herstellung |
| FR2678832B1 (fr) * | 1991-07-10 | 1995-03-17 | Europhta Sa Laboratoire | Nouvelles compositions ophtalmiques a resorption amelioree et leurs procedes de preparation. |
| FR2679773A1 (fr) * | 1991-07-30 | 1993-02-05 | Merck Sharp & Dohme | Preparation ophtalmique contenant un agent osmotique acceptable antimicrobien. |
| DE19614823A1 (de) * | 1996-04-15 | 1997-10-16 | Mann Gerhard Chem Pharm Fab | Ophthalmische Zusammensetzung mit verlängerter Verweilzeit am Auge |
-
1999
- 1999-02-03 IN IN90BO1999 patent/IN185228B/en unknown
-
2000
- 2000-02-02 AP APAP/P/2000/001977A patent/AP2000001977A0/en unknown
- 2000-02-02 CA CA002326690A patent/CA2326690A1/en not_active Abandoned
- 2000-02-02 BR BR0004530-6A patent/BR0004530A/pt not_active Application Discontinuation
- 2000-02-02 EP EP00925571A patent/EP1139970A2/en not_active Withdrawn
- 2000-02-02 IL IL13882400A patent/IL138824A0/xx unknown
- 2000-02-02 EA EA200000918A patent/EA200000918A1/ru unknown
- 2000-02-02 WO PCT/IN2000/000008 patent/WO2000049990A2/en not_active Application Discontinuation
- 2000-02-02 AU AU44291/00A patent/AU4429100A/en not_active Abandoned
- 2000-02-02 ID IDW20002252A patent/ID28121A/id unknown
- 2000-11-01 ZA ZA200006252A patent/ZA200006252B/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2007091A (en) * | 1977-11-07 | 1979-05-16 | Toko Yakuhin Kogyo Kk | Ophthalmic composition |
Also Published As
| Publication number | Publication date |
|---|---|
| AP2000001977A0 (en) | 2000-12-31 |
| AU4429100A (en) | 2000-09-14 |
| ID28121A (id) | 2001-05-03 |
| EA200000918A1 (ru) | 2001-10-22 |
| WO2000049990A3 (en) | 2001-07-26 |
| CA2326690A1 (en) | 2000-08-31 |
| WO2000049990A2 (en) | 2000-08-31 |
| IN185228B (enrdf_load_stackoverflow) | 2000-12-09 |
| IL138824A0 (en) | 2001-10-31 |
| BR0004530A (pt) | 2001-04-03 |
| ZA200006252B (en) | 2001-11-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2588078B1 (fr) | Systeme de delivrance polymerique d'une solution non visqueuse a base de prostaglandine sans conservateur | |
| US5188826A (en) | Topical ophthalmic suspensions | |
| US5710182A (en) | Ophthalmic composition | |
| EP1028707B1 (en) | Sustained release ophthalmic compositions containing water soluble medicaments | |
| EP2109442B1 (en) | Ophthalmic compositions containing a synergistic combination of three polymers | |
| US5795913A (en) | Ophthalmic composition | |
| US7914803B2 (en) | Ophthalmic compositions containing a synergistic combination of three polymers | |
| EP1139970A2 (en) | The process for manufacturing topical ophthalmic preparations without systemic effects | |
| US8313754B2 (en) | Ophthalmic compositions containing a synergistic combination of two polymers | |
| Chang et al. | Relative effectiveness of prodrug and viscous solution approaches in maximizing the ratio of ocular to systemic absorption of topically applied timolol | |
| WO2011018800A2 (en) | A novel in-situ gel forming solution for ocular drug delivery | |
| CN103079595B (zh) | 滴眼用水性组合物 | |
| US20110003816A1 (en) | Ophthalmic composition | |
| EP1189595B1 (en) | Ophthalmic compositions in form of aqueous gels | |
| Rathore et al. | Preparation and characterization of timolol maleate ocular films | |
| CN103977011B (zh) | 含有曲伏前列素和噻吗洛尔的眼用凝胶剂及其制备方法 | |
| MXPA00009715A (en) | The process for manufacturing topical ophthalmic preparations without systemic effects | |
| JP2013129604A (ja) | 緑内障治療薬を含有する徐放性フィルム製剤 | |
| WO2024241345A1 (en) | Ophthalmic suspension composition of brinzolamide and latanoprost | |
| HK1013953B (en) | Ophthalmic composition with decreased viscosity | |
| HK1178446B (en) | Polymeric delivery system for a nonviscous prostaglandin-based solution without preservatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| 17P | Request for examination filed |
Effective date: 20010813 |
|
| AK | Designated contracting states |
Kind code of ref document: A2 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE |
|
| AX | Request for extension of the european patent |
Free format text: AL PAYMENT 20001024;LT PAYMENT 20001024;LV PAYMENT 20001024;MK PAYMENT 20001024;RO PAYMENT 20001024;SI PAYMENT 20001024 |
|
| 17Q | First examination report despatched |
Effective date: 20031205 |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
| 18D | Application deemed to be withdrawn |
Effective date: 20050316 |