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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• • 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

Definitions

• the present invention provides an ophthalmic composition for topical application comprising a mydriatic agent and a viscoelastic polymer, and also methods of preparing such a composition for human and veterinary administration.
• the dilatation of pupil has different indications e.g. fundus examinations, old age refractions, for visual gain in cataract etc.
• Mydriasis-use of phenylephrine (a dose-response concept) , Chawdhary S, Angra SK, Zutshi R, Sachdev MS, Indian Journal of Ophthamology, 1984, vol 32, issue 4, 213 -16)
• Phenylephrine is recommended as a vasoconstrictor, decongestant and mydriatic for a wide variety of ophthalmic conditions and procedures.
• a mydriatic is an agent which induces dilation of the pupil. Some of its uses are for pupillary dilation in uveitis, for many surgical procedures and for refraction without cycloplegia. It may also be used
• Phenylephrine is a very unstable compound in solution and is found to degrade in the presence of light and upon atmospheric contact. Phenylephrine hydrochloride and solutions containing the drug are subject to oxidation and should be stored in tight, light-resistant containers. Solutions of the drug must not be used if they are brown or contain a precipitate. However, oxidation of the drug resulting in loss of activity may occur without a color change being evident. In the prior art, various compositions comprising phenylephrine have been prepared. However, none address problem of oxidation.
• An object of the present invention is to provide an ophthalmic composition comprising phenylephrine, a mydriatic agent and a viscoelastic agent.
• Yet another object of the invention is to provide a process for the preparation of the ophthalmic drug.
• the present invention provides an ophthalmic composition
• phenylephrine a viscoelastic agent, an osmolality agent, an ophthalmically acceptable salt, a buffering agent and water.
• the phenylephrine may be present in the range of 0.15%w/v - 10% w/v.
• Phenylephrine may be in the form of pharmaceutically acceptable salt such as the salt of inorganic acid hydrochloride, bicarbonate, sulfate, nitrate etc or salt of organic acid such as tartarate, acetate, etc.
• the composition comprises a viscoelastic agent that is preferably selected from the group of carboxyl methyl cellulose, poly vinyl alcohol, hydroxy propyl methyl cellulose (HPMC), hydroxy ethyl cellulose, povidone, dextran, etc.
• a viscoelastic agent that is preferably selected from the group of carboxyl methyl cellulose, poly vinyl alcohol, hydroxy propyl methyl cellulose (HPMC), hydroxy ethyl cellulose, povidone, dextran, etc.
• HPMC hydroxy propyl methyl cellulose
• HPMC hydroxy ethyl cellulose
• povidone povidone
• dextran etc.
• the amount of the viscoelastic agent, i.e. such as HPMC contained in the composition is 0.1-3%, preferably 0.2-1%, and most preferably 0.2-0.5%.
• the viscosity of the composition of the present invention may be 0.1-10 cps, preferably 0.5-5 cps, and most preferably 1-3 cps. This relatively low viscosity ensures that the product is comfortable, does not cause blurring, and is easily processed during manufacturing, transfer and filling operations
• the composition optionally further includes at least one ophthalmically acceptable salt in an amount required to bring osmolality of the composition into an ophthalmically acceptable range.
• ophthalmically acceptable salt include those having sodium, potassium or ammonium cation and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anion; preferred salt include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate, with sodium chloride being especially preferred.
• solutes suitable for adjustment of osmolality include sugar, for example dextrose, lactose, xylitol, mannitol and glycerine.
• composition as described herein above also comprises a buffering agent and/or an agent for adjusting osmolality in amounts whereby the solution is substantially isotonic and has a physiologically acceptable pH.
• composition also includes an agent for normalizing the osmolality such as sodium citrate.
• Ophthalmicaly acceptable osmolality lies within the limits of 150-1150 mOsm, preferably within 250-450 mOsm, most preferably within the limits of 300-400 mOsm
• the composition of the invention optionally further includes at least one ophthalmically.
• acceptable pH adjusting agent and/or buffer including an acid such as acetic, boric, citric, lactic, phosphoric and hydrochloric acid; a base such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane, triethanolamine; and a buffer such as citrate/dextrose, sodium bicarbonate and ammonium chloride, or an amino acid.
• an acid, base and/or buffer is preferably included in an amount required to maintain pH of the composition in an ophthalmically acceptable range.
• the pH of the composition of the present invention may be between 3-8, preferably within the range of 4-7 and most preferably in the range of 4.0-5.5.
• the amount of salt, buffer required for adjusting the osmolality and the pH, respectively is well known to those skilled in the art.
• composition of the present invention is preferably packaged in opaque plastic container, one that can be presented in the form of eye drops packed in glass vial preferably amber colored, BFS plastic vial desirably opaque or three-piece plastic vial preferably opaque.
• composition of the present invention may be prepared by a process comprising
• a solution of HPMC, buffering agent and osmolality agent may be prepared by simple admixture, with agitation as appropriate, of the ingredients. Buffering agents and agents for adjustment of osmolality can be added at any stage but are preferably present in solution with the HPMC before addition of the Phenylephrine
• the aqueous solution containing HPMC 5 buffering agent and osmolality agent is first prepared, and the Phenylephrine is added to that solution with agitation until it is fully dissolved.
• Processes for preparing an ophthalmic composition of the invention are preferably conducted in a sterile environment so as to provide a sterile product.
• composition of the type as illustrated by the present invention has been found to be - substantially stable and efficacious to the compositions without viscoelastic agent.
• Example 2 Effect of composition on dilation of eye in rabbits.
• Example 1 The composition of Example 1 was prepared. Another composition similar to that of Example 1 was prepared but, without HPMC. The effect of composition with HPMC was compared with the composition without HPMC. The mydriatic effect of the composition was studied by examining the pupil dilatation activity in New Zealand albino rabbits weighing about 2.5-3 kg and is given in Table I.
• the rabbits were divided in to two groups of 6 each. Left eye of each rabbit was kept as control and one drop of 0.9% sodium chloride isotonic saline solution was instilled. In the right eye one drop of composition of present invention with viscoelastic and without viscoelastic agent was instilled. The pupil size, light reflux, corneal reflux and state of conjunctiva was observed and recorded at 0 minute (Control value), 15 min, 30 min, 45 min, 60 min, then at hourly interval for 6 hrs. The results are provided in table " 1. '
• the above table measures dilation of the pupil and the time required for dilation of the pupil.
• An increase in the value of dilation and decrease in the time required for dilation shows enhanced efficacy of the composition.
• the period of peak dilation indicates the duration of efficacy of the drug while the time to reach peak dilation is indicated by time of peak dilation. Lower the peak dilation time indicates the higher efficacy.
• Example 3 It was found that addition of HPMC improves the appearance and controls the level of impurities in the phenylepherine composition and hence it increased the overall shelf life of the product as described in Table -2

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• Health & Medical Sciences (AREA)
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• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 2008
  • 2008-10-07 WO PCT/IB2008/002647 patent/WO2009074853A2/en active Application Filing
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