Classifications

• • 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
• • 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

Definitions

• the present invention is related to the field of slow release drug delivery systems for therapeutic use, especially in the ophthalmic field, and provides an aqueous liquid composition which in contact with a physiological solution forms a gel matrix which has been found to stay for a considerable time in the administration area, for instance the eye, without causing any problems to the patient.
• This gel can be utilized for controlled continuous administration of drug over a prolonged period of time.
• a composition according to the invention can be used in a number of situations, e.g. oral, buccal, nasal and vaginal administration, when a slow release system is advantageous but will in the following be discussed mainly in connection with it's ophthalmological use since the requirements here are especially high.
• a solid implant containing the active drug is manufactured and delivered to the doctor or nurse for application onto the patient's conjunctiva, preferably under one of the eye lids.
• These type of implants often have an outer membrane layer through which the drug is allowed to diffuse. The release rate depends on the membrane structure as well as the internal matrix in which the drug is incorporated.
• compositions which at room temperature and below this value is liquid (non-solid) is instilled into the eye and due to the rise in temperature forms a polymer matrix, for instance a gel.
• a polymer matrix for instance a gel.
• Some systems have been disclosed which are physiologically acceptable and which form a gel in contact with a physiological salt solution, for instance a tear solution. It is readily appreciated that according to this concept potentially very useful systems for drug delivery are provided.
• compositions of the type mentioned above in contrast to the teaching of the prior art are made hypotonic. Gels formed under these conditions have been found to stay considerably longer in the eye compared to gels formed at higher tonicity values, e.g. under isotonic conditions, hence providing a more efficient delivery system.
• the invention is accordingly related to a liquid hypotonic ophthalmic solution comprising a pharmaceutically active drug and at least one hydrophilic polymer of the type which undergoes liquid-gel phase transition gelling in situ in contact with the physiological solution, for instance tear solution or humour solution when used for intraocular administration.
• a method for administration of a drug is provided using a composition as defined in this specification.
• the hydrophilic polymer is functionally defined by the ability of an aqueous solution of the polymer to form a solid polymer structure, for instance a gel, when the ionic strength is raised to physiological values.
• components belonging to this group include polysaccharides and natural as well as synthetic polysaccharide derivatives.
• the preferred component at present is an extracellular anionic heteropolysaccharide produced by the bacterium Pseudo onas elodea, known as gellan gum and marketed as GelriteTM.
• the gel forming component may in more general terms be any component which before administration is a liquid but forms a gel upon contact with a physiological fluid due to exchange of components between said liquid and the physiological fluid.
• Such exchange of components include but is not limited to proteins, such as lysozymes, and ionic components as discussed above.
• concentration of the gel forming component in cases when Gelrite is used is preferably in the range of from 0.1 to 10 % by weight, especially 0.1-2 % by weight.
• the non- solid composition containing the hydrophilic polymer solution is hypotonic. It has been found, however, that the tonicity should not be too low since this causes undesirable side- effects, such as more or less severe initial irritation when the composition is applied.
• the osmolality of the non-solid composition should accordingly be lower than that of an isotonic solution (about 290 mOs/kg) and a selected range according to this invention is from about 25 - 200 mOs/kg, preferably 25-150 mOs/kg and especially 50-150 mOs/kg.
• the at present most prefered composition has a value around 100 mOs/kg.
• the drug component contained in the composition should preferably be present as a dispersive system, either as a suspension of particles or as an emulsion.
• the drug could be incorporated in or associated with carrier substances in the form of particles e.g. polymers (biodegradable, non- biodegradable or polymers which dissolve or degrade upon contact with a physiological fluid) , lipids or ion-exchange resins.
• EP424042 is disclosed a system based on compositions of the Gelrite type in which the drug is present in particles which dissolve due to change in pH when the composition is instilled into the eye.
• the pH and the buffering capacity of the composition being such that the neutralizing action of lachrymal fluid is sufficient for dissolving the solid microparticles.
• the drug component contained in the composition could also be present as a solution. It may be solubilized by surfactants, lipids or by complex-forming agents.
• the active drug to be administered according to the present invention can be chosen among a great number of components, for instance for ophthalmological use.
• examples of such components include
• - antihistaminics and decongestants for instance pyrilamine, tetrahydrazoline, antazoline and analogues thereof,
• - anti-inflammatories such as flubiprofen, diclofenac, acetylsalicylic acid, cortisone, hydrocortisone, dexamethasone, prednisone, indomethacin and analogues thereof
• antibacterial substances such as tetracyclines, penicillin, bacitracin, sulphonamides and analogues thereof,
• cytotoxics for instance 5-fluorouracil
• - antiglaucoma drugs for instance prostaglandins like the omega chain modified derivatives disclosed in EP0364417 (esp. 13, 14-dihydro-17-phenyl-18, 19,20-trinor-PGF2 ⁇ -isopropylester) and timolol, pilocarpine, epinephrine, dipivalylepinephrine, and their analogues.
• prostaglandins like the omega chain modified derivatives disclosed in EP0364417 (esp. 13, 14-dihydro-17-phenyl-18, 19,20-trinor-PGF2 ⁇ -isopropylester) and timolol, pilocarpine, epinephrine, dipivalylepinephrine, and their analogues.
• composition may contain other additives such as polymers, preservatives, nonionic tonicity agents, solubilizers, buffer agents, complexing agents and chelating agents.
• additives such as polymers, preservatives, nonionic tonicity agents, solubilizers, buffer agents, complexing agents and chelating agents.
• the composition also contained a small amount of fluorescent particles. The time these particles were detectable in the instillation area was measured and taken as an indication of the effectiveness of the drug delivery system.
• a glycerol concentration of 3% is close to an isotonic solution and represents a comparison with a prior art system.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Preparation (AREA)
• Inorganic Chemistry (AREA)
• Ophthalmology & Optometry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Applications Claiming Priority (3)

Publications (1)

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• 1993
  • 1993-06-02 SE SE9301877A patent/SE9301877D0/xx unknown
• 1994
  • 1994-06-01 CA CA 2164113 patent/CA2164113A1/en not_active Abandoned
  • 1994-06-01 EP EP94917868A patent/EP0706372A1/de not_active Withdrawn
  • 1994-06-01 JP JP7500555A patent/JPH08510731A/ja active Pending
  • 1994-06-01 AU AU69405/94A patent/AU6940594A/en not_active Abandoned
  • 1994-06-01 WO PCT/SE1994/000522 patent/WO1994027578A1/en not_active Application Discontinuation

Non-Patent Citations (1)

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