ZA200006252B - The process for manufacturing topical ophthalmic preparations without systemic effects. - Google Patents
The process for manufacturing topical ophthalmic preparations without systemic effects. Download PDFInfo
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- ZA200006252B ZA200006252B ZA200006252A ZA200006252A ZA200006252B ZA 200006252 B ZA200006252 B ZA 200006252B ZA 200006252 A ZA200006252 A ZA 200006252A ZA 200006252 A ZA200006252 A ZA 200006252A ZA 200006252 B ZA200006252 B ZA 200006252B
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- South Africa
- Prior art keywords
- formulation
- drug
- polymer
- topical ophthalmic
- ophthalmic preparations
- Prior art date
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- 230000000699 topical effect Effects 0.000 title claims description 28
- 238000002360 preparation method Methods 0.000 title claims description 27
- 230000009885 systemic effect Effects 0.000 title claims description 25
- 238000000034 method Methods 0.000 title claims description 15
- 230000008569 process Effects 0.000 title claims description 13
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- 229940079593 drug Drugs 0.000 claims description 26
- 239000003814 drug Substances 0.000 claims description 26
- 229920000642 polymer Polymers 0.000 claims description 11
- 238000009472 formulation Methods 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 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
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- 230000003232 mucoadhesive effect Effects 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 229920002125 Sokalan® Polymers 0.000 claims 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims 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 claims 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims 1
- 229920002907 Guar gum Polymers 0.000 claims 1
- 229920000148 Polycarbophil calcium Polymers 0.000 claims 1
- 239000007864 aqueous solution Substances 0.000 claims 1
- 239000007900 aqueous suspension Substances 0.000 claims 1
- 229960001631 carbomer Drugs 0.000 claims 1
- 229940075510 carbopol 981 Drugs 0.000 claims 1
- 239000001913 cellulose Substances 0.000 claims 1
- 229920002678 cellulose Polymers 0.000 claims 1
- 239000000839 emulsion Substances 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 239000013020 final formulation Substances 0.000 claims 1
- 239000000665 guar gum Substances 0.000 claims 1
- 229960002154 guar gum Drugs 0.000 claims 1
- 235000010417 guar gum Nutrition 0.000 claims 1
- 238000012856 packing Methods 0.000 claims 1
- 239000004584 polyacrylic acid Substances 0.000 claims 1
- 229950005134 polycarbophil Drugs 0.000 claims 1
- 229940068984 polyvinyl alcohol Drugs 0.000 claims 1
- 238000003756 stirring Methods 0.000 claims 1
- 229920001567 vinyl ester resin Polymers 0.000 claims 1
- 229920001285 xanthan gum Polymers 0.000 claims 1
- 230000000694 effects Effects 0.000 description 5
- 230000036470 plasma concentration Effects 0.000 description 5
- 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
- 239000000243 solution Substances 0.000 description 4
- 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 3
- 239000004480 active ingredient Substances 0.000 description 3
- 210000002850 nasal mucosa Anatomy 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 229960004605 timolol Drugs 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 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
- 229960002896 clonidine Drugs 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
- 239000002904 solvent Substances 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
- 241000283973 Oryctolagus cuniculus Species 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
- 229960004324 betaxolol Drugs 0.000 description 1
- NWIUTZDMDHAVTP-UHFFFAOYSA-N betaxolol Chemical compound C1=CC(OCC(O)CNC(C)C)=CC=C1CCOCC1CC1 NWIUTZDMDHAVTP-UHFFFAOYSA-N 0.000 description 1
- 230000005540 biological transmission 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
- 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
- 239000006196 drop Substances 0.000 description 1
- 206010013781 dry mouth Diseases 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops 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
- 230000036543 hypotension Effects 0.000 description 1
- 230000001077 hypotensive effect Effects 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
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 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
- 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
- 230000006794 tachycardia Effects 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
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Ophthalmology & Optometry (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Description
THE PROCESS FOR MANUFACTURING TOPICAL OPHTHALMIC PREPARATIONS
WITHOUT SYSTEMIC EFFECTS.
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, B-blockers like Timolol, Betaxolol, etc. Some of these drugs 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.
Examples of well known systemic effects of topical ophthalmic preparations include cardiopulmonary effects of p-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. Increased salivation, nausea, vomiting, diarrhoea, stomach cramp, bronchial secretions, bronchial constriction, asthma, bradycardia, parasthesia is seen with miotics.
Systemic hypotension is main limiting factor for use of clonidine in management of glaucoma. Dry mouth, fatigue and drowsiness seen with Brimonidine and
Apraclonidine are some of their systemic effects.
The systemic side effects, manifesting with the use of topical ophthalmic preparations results in discontinuation of therapy or not initiating a therapy or reducing the amount of drug or drug not having wide spread acceptance. :
Because of this reason, attempts’ are made to reduce systemic effects of topically - applied drugs.
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.
eGGGSSSSSSSSSSESSSSSSEESS———_——
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.
None of the above described methods in isolation or in combination with each- other have been successful in eliminating systemic effects of topical ophthalmic preparations. Majority of efforts are centered around topical B-blockers to reduce their systemic effect, e.g. reduction in pulse rate. All known methods have been able to decrease the reduction in pulse rate, but none of them have been able to eliminate it completely.
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Evaluativon of viscous ophthalmic vehicles containing carbomer by slit- lamp fluorophotometry in humans.
International Journal of Pharmaceutics 1990; 61: 15-25. 2. Arto Urtti, James D Pipkin, Gerald Rork, Toshiaki Sendo, Ulha Finne and
Al Repta.
Contyrolled drug delivery devices for experimental ocular studies with timolol. 2. Ocular and systemic absorption in rabbits. :
International Journal of Pharmaceutics 1990; 61: 241-249, 3. Benedetto DA, Shah DO,-Kaufman HE.
The instilled fluid dynamics and surface chemistry of polymers in the preocular tear film.
Invest Ophthamol 1975 Dec; 14(12): 887-902. 4. Chang SC, Lee VH.
Nasal and conjunctival contributions to the systemic absorption of topical timolol in the pigmented rabbit: implications in the design of strategies to maximise the ratio of ocular to systemic absorption.
J Ocular Pharmacol 1987 Summer; 3(2): 159-69. 5. Chiang CH, Ho JI, Chen JL.
Pharmacokinetics and intraocular pressure lowering effect of timolol preparations in rabbit eyes.
J Ocul Pharmacol Ther 1996 Winter; 12(4): 471-80. 6. Jarvinen K, Urtti A.
Cardiac effects of different eyedrop preparations of timolol in rabbits.
Curr Eye Res 1992 May; 11(5): 469-73.
7. Johansen S, Rask-Pedersen E, Prause JU.
A bioavailability comparison in rabbits after a single topical ocular application of prednisolone acetate formulated as a high-viscocity gel and as a aqueous suspension.
Acta Ophthalmol Scand 1996 June; 74(3): 253-8 8. Johansen S, Rask-Pedersen E, Prause JU. :
An ocular bioavailability comparison in rabbits of prednisolone acetate after repeated topical applications formulated as a high-viscocity gel and as an aqueous suspension.
Acta Ophthalmol Scand 1996 June; 74(3): 259-64. 9. Kumar V, Schoenwald RD, Barcellos WA, Chien DS, Folk JC, Weingeist
TA.
Aqueous vs viscous phenylephrine. I. Systemic absorption and cardiovascular effects.
Arch Ophthalmol 1986 Aug; 104(8): 1189-91. 10. Kumar S, Himmelstein KI.
Modification of in situ gelling behaviour of carbopol solutions by’ hydroxypropyl methyl cellulose.
J Pharm Sci 1995 Mar; 84(3): 344-8. 11. Kyyronen K, Urtti A.
Improved ocular: systemic absorption ratio of timolol by viscous vehicle and phenylephrine.
Invest Ophthalmol Vis Sci 1990 Sep; 31(9): 1827-33. 12. Marco F Saetonne, Patrizia Chetoni, Maria Tilde Torracca, Susi Burgalassi and Boris Giannaccini. :
Evaluation of muco-adhesive properties and in vivo activity of ophthalmic vehicles based on hyaluronic acid.
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Ocular absorption and distribution of benzadac after topical administration : to rabbits with different vehicles.
Life Sci 1994; 54(13): 877-85. 14. Sieradzki E.
Bioavailability of drugs applied to the eye externally [Article in Polish]. ‘Klin Oczna 1991 jan; 93(1): 34-6. 15. Urtti A.
Delivery of antiglaucoma drugs: ocular vs systemic absorption.
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Minimizing systemic absorption of topically administered ophthalmic drugs.
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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.
Accordingly there is provided a process of manufacturing topical ophthalmic preparations without systemic side effects which comprises of the following steps. 1. 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. 2. In a separate vessel polymer is dissolved into a solvent preferably water and stirred well till gel is formed. 3. Solution containing selected drug as formulated in step 1 is gradually added to the gel as formed in step 2.
4. Volume is made up by adding distilled water/solvent as required. 5. 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 B-blockers like Timolol,
Levobunolol, Metipranalol, etc.
Similarly, 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 1.0.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. For the purpose of present invention it is desirable to select a polymer with mucoadhesive properties. To avoid discomfort and visual disturbances associated with use of viscous solutions, it is desirable that polymer selected demonstrates pseudoplastic behaviour in a formulation.
Claims (10)
1. The process of manufacturing of formulation of topical ophthalmic preparations without systemic effect comprising the following steps.
1. Making a gel using polymers with or without physiologically acceptable excipients buffers and preservatives il. Adding liquid formulation of a drug into a prepared gel of step (i) while stirring slowly.
ii. Adjusting the pH and volume before final packing
2. A process as claimed in claim 1 wherein Polymer can be any polymer havin g pseudoplastic behaviour.
3. A process as claimed in claim 1 & 2 wherein polymer should have mucoadhesive property.
4. A process as claimed in claim | to 3 wherein polymer can be but not restricting to Carbopol 940 (Polyacrylic acid), Carbopol ETD 2001, Carbopol 981, Polycarbophil, Polyvinyl Alcohol, Hydroxyethyl. Cellulose, Polyacrylic esters, Acrypol, Xantham gum, Guar gum, poly- vinyl ester, Carbomer etc.
5. Polymer as claimed in claim 1 to 4 can be used alone or in combination with other polymers.
6. The process as claimed in claim 1 to 5 wherein viscosity of final’ : formulation is more than 100,000 cps (One hundred thousand cps).
7. The process as claimed in claim 1 to 6 physiologically acceptable buffers excipients and preservatives are used. :
8. The process as claimed in claim 1 to 7 wherein liquid formulation of a drug can be in the form of aqueous solution, suspension or emulsion.
0. The process as claimed in claim 1 to 8 wherein volume of formulation is adjusted to get desired concentration of a drug into final formulation.
10. A process as claimed in claim 1 to 9 and substantially described in example in accompanying specification. :
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN90BO1999 IN185228B (en) | 1999-02-03 | 1999-02-03 |
Publications (1)
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| ZA200006252B true ZA200006252B (en) | 2001-11-29 |
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| ZA200006252A ZA200006252B (en) | 1999-02-03 | 2000-11-01 | The process for manufacturing topical ophthalmic preparations without systemic effects. |
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| EP (1) | EP1139970A2 (en) |
| AP (1) | AP2000001977A0 (en) |
| AU (1) | AU4429100A (en) |
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| CA (1) | CA2326690A1 (en) |
| EA (1) | EA200000918A1 (en) |
| ID (1) | ID28121A (en) |
| IL (1) | IL138824A0 (en) |
| IN (1) | IN185228B (en) |
| WO (1) | WO2000049990A2 (en) |
| ZA (1) | ZA200006252B (en) |
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| US8858961B2 (en) | 2000-07-14 | 2014-10-14 | Allergan, Inc. | Compositions containing alpha-2-adrenergic agonist components |
| AU2005220199B2 (en) * | 2000-07-14 | 2007-03-08 | Allergan, Inc. | Compositions containing alpha-2-adrenergic agonist components |
| NZ521185A (en) * | 2000-07-14 | 2005-02-25 | Allergan Inc | Compositions containing alpha-2-adrenergic agonist components |
| DE10132876A1 (en) * | 2001-07-06 | 2003-01-30 | Medproject Pharma Entwicklungs | Two-phase, drop-onable hydrogels for use on the eye |
| US7439241B2 (en) | 2003-05-27 | 2008-10-21 | Galderma Laboratories, Inc. | Compounds, formulations, and methods for treating or preventing rosacea |
| ES2647618T3 (en) | 2004-05-25 | 2017-12-22 | Galderma Pharma S.A. | Compounds, formulations and procedures to treat or prevent inflammatory skin disorders |
| 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 (en) | 2011-07-05 | 2014-02-14 | Galderma Res & Dev | NOVEL STABLE ANESTHETIC COMPOSITION FOR REDUCING SKIN REACTIONS |
| WO2014127243A1 (en) | 2013-02-15 | 2014-08-21 | Allergan, Inc. | Sustained drug delivery implant |
| 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 |
| US11052094B2 (en) | 2015-05-29 | 2021-07-06 | Sydnexis, Inc. | D2O stabilized pharmaceutical formulations |
| GB202110420D0 (en) * | 2021-07-20 | 2021-09-01 | Rosemont Pharmaceuticals Ltd | Liquid pharmaceutical composition of clonidine |
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| JPS6056684B2 (en) * | 1977-11-07 | 1985-12-11 | 東興薬品工業株式会社 | eye drops |
| DD294174A5 (en) * | 1990-05-04 | 1991-09-26 | Sigrid Keipert | OPHTHALMIKA WITH RESET EFFECT AND A NEW PROCESS FOR THEIR MANUFACTURE |
| FR2678832B1 (en) * | 1991-07-10 | 1995-03-17 | Europhta Sa Laboratoire | NOVEL OPHTHALMIC COMPOSITIONS WITH IMPROVED RESORPTION AND METHODS OF PREPARING THE SAME. |
| FR2679773A1 (en) * | 1991-07-30 | 1993-02-05 | Merck Sharp & Dohme | Ophthalmic preparation containing an acceptable antimicrobial osmotic agent |
| DE19614823A1 (en) * | 1996-04-15 | 1997-10-16 | Mann Gerhard Chem Pharm Fab | Ophthalmic composition with prolonged retention time on the eye |
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1999
- 1999-02-03 IN IN90BO1999 patent/IN185228B/en unknown
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2000
- 2000-02-02 AP APAP/P/2000/001977A patent/AP2000001977A0/en unknown
- 2000-02-02 ID IDW20002252A patent/ID28121A/en unknown
- 2000-02-02 EP EP00925571A patent/EP1139970A2/en not_active Withdrawn
- 2000-02-02 AU AU44291/00A patent/AU4429100A/en not_active Abandoned
- 2000-02-02 IL IL13882400A patent/IL138824A0/en unknown
- 2000-02-02 CA CA002326690A patent/CA2326690A1/en not_active Abandoned
- 2000-02-02 EA EA200000918A patent/EA200000918A1/en unknown
- 2000-02-02 WO PCT/IN2000/000008 patent/WO2000049990A2/en not_active Application Discontinuation
- 2000-02-02 BR BR0004530-6A patent/BR0004530A/en active Pending
- 2000-11-01 ZA ZA200006252A patent/ZA200006252B/en unknown
Also Published As
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| IN185228B (en) | 2000-12-09 |
| WO2000049990A3 (en) | 2001-07-26 |
| AU4429100A (en) | 2000-09-14 |
| EA200000918A1 (en) | 2001-10-22 |
| IL138824A0 (en) | 2001-10-31 |
| ID28121A (en) | 2001-05-03 |
| EP1139970A2 (en) | 2001-10-10 |
| WO2000049990A2 (en) | 2000-08-31 |
| AP2000001977A0 (en) | 2000-12-31 |
| BR0004530A (en) | 2001-04-03 |
| CA2326690A1 (en) | 2000-08-31 |
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