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.

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• 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)

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• 1999
  • 1999-02-03 IN IN90BO1999 patent/IN185228B/en unknown
• 2000
  • 2000-02-02 EP EP00925571A patent/EP1139970A2/de not_active Withdrawn
  • 2000-02-02 BR BR0004530-6A patent/BR0004530A/pt active Pending
  • 2000-02-02 AP APAP/P/2000/001977A patent/AP2000001977A0/en unknown
  • 2000-02-02 ID IDW20002252A patent/ID28121A/id unknown
  • 2000-02-02 AU AU44291/00A patent/AU4429100A/en not_active Abandoned
  • 2000-02-02 IL IL13882400A patent/IL138824A0/xx unknown
  • 2000-02-02 WO PCT/IN2000/000008 patent/WO2000049990A2/en not_active Application Discontinuation
  • 2000-02-02 CA CA002326690A patent/CA2326690A1/en not_active Abandoned
  • 2000-02-02 EA EA200000918A patent/EA200000918A1/ru unknown
  • 2000-11-01 ZA ZA200006252A patent/ZA200006252B/en unknown

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