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

Definitions

• the present invention relates to an ophthalmological composition containing at least one polysaccharide in aqueous solution, of the type which undergoes liquid-gel phase transition under the effect of an increase in the ionic strength. They are particularly intended for contacting with lacrimal fluid.
• galenical forms can be used which are liquid at room temperature and assume a semi-solid form at human body temperature.
• Such delivery systems are described in US Patent 4,188,373, which propose the use of "PLURONICTM polyols".
• PLURONICTM polyols are thermally gelling polymers in which the polymer concentration is chosen in accordance with the desired liquid-gel transition temperature.
• PLURONICTM polyols it is difficult to obtain a gel of suitable rigidity while maintaining the transition temperature at physiological temperatures.
• Canadian Patent 1,072,413 describes systems where the gelification temperatures are made higher than room temperature by using additives.
• thermally gelling systems have many disadvantages, including the risk of gelling before administration by an increase in the ambient temperature during packaging or storage, for example.
• US Patent 4,474,751 of Merck & Co.. relates to other systems for delivering drugs based on thermogelification of gels, but these systems require very large amounts of polymers and this is not always well tolerated by the eye.
• European patent specification No. 0 227 494-A describes ophthalmological compositions comprising polysaccharides of the type which undergo liquid-gel phase transition gelling in situ under the effect of an increase in the ionic strength of the lacrimal fluid.
• Specific examples of ophthalmological compositions comprising gellan gum are taught as the basis of ready-to-use solution and, in particular, compositions comprising the anti-glaucoma agent, timolol.
• Pilocarpine is only stable in acid, aqueous solutions (pH ⁇ 5.0) therefore, in general, conventional pilocarpine ophthalmological compositions are prepared as viscous or non-viscous, ready-to-use solutions at or below pH 5.0.
• Pilocarpine has been formulated as an aqueous gel.
• Pilopine HSTM Gel for example, is an aqueous gel, at pH 4.8, which may be applied once a day.
• gels are difficult to apply and can cause blurred vision. For these reasons, they are less well accepted by patients than solutions.
• the present invention relates to an ophthalmological composition intended for contacting with the lacrimal fluid where said composition is intended to be administered as a non-gelled liquid form and is intended to gel in situ, this composition containing at least one polysaccharide in aqueous solution, of the type which undergoes liquid-gel phase transition gelling in situ under the effect of an increase in the ionic strength of said lacrimal fluid and a pharmaceutically active substance characterised in that said pharmaceutically active substance is pilocarpine or a pharmaceutically acceptable salt thereof, wherein said composition comprises a first component which is an acid aqueous solution of pilocarpine and a second component which is a neutral or alkaline aqueous solution of a polysaccharide of the type which undergoes liquid-gel phase transition under the effect of an increase in the ionic strength, said components being mixed extemporaneously at the time of first use.
• composition of the present invention which takes the form of a liquid before its introduction into the eye, undergoes a liquid-gel phase transition, and hence changes from the liquid phase to the gel phase, once it is introduced into the eye, as a result of the ionic strength of the lacrimal fluid.
• This new ophthalmological composition is an advantageous form for several reasons.
• the polymer used can form a gel at concentrations 10- to 100- fold lower than those used in systems involving thermogelification. It is hence very well tolerated by the eye.
• the formulation has the advantage of a pH in the range of 6.5-6.8, and ideally at about pH 6.7, thus providing the optimum conditions for ocular bioavailability and tolerance of pilocarpine.
• the bioavailability is further enhanced by the presence of the polysaccharide. Therefore, the - -
• compositions of the present invention which are administered as a drop which then forms a temporary gel layer in the conjunctival sac make it possible to achieve great bioavailability of the pilocarpine at concentrations which are sustained with time. Furthermore, in the case of already gelled or semi-solid compositions, it is not possible to administer them by volumetric means, especially when they come from a multi-dose container.
• compositions according to the invention have, on the one hand, the advantage of liquid ophthalmic compositions, namely reproducible and accurate dosing, by volumetric means, of the pilocarpine, and on the other hand the advantages known for the systems in rigid or semi-solid gel form, relating to the delivery of active substances.
• composition according to the invention consequently has neither the disadvantages of losses of active substances characteristic of simple liquid compositions, nor the unpleasant aspects of solid implant systems, nor finally the difficulties of administration associated with gelled or semi-solid compositions.
• aqueous polysaccharide solutions of the type which undergoes liquid-gel phase transition under the effect of an increase in the ionic strength, which are especially suitable according to the invention, are solutions of a polysaccharide obtained by fermentation of a microorganism.
• an extracellular anionic heteropolysaccharide elaborated by the bacterium Pseudomonas elodea and known by the name gellan gum is preferably used.
• this heteropolysaccharide consists of the following tetrasaccharide repeating unit: ⁇ 3)- ⁇ -D-Glcp-(l ⁇ 4)- ⁇ -D-GlcpA-(l ⁇ 4)- ⁇ -D-Glcp-(l ⁇ 4)- ⁇ -L-Rhap-(l ⁇
• aqueous solutions containing about 0.1% to about 2.0% by weight of gellan gum, and especially of the product known by the tradename GelriteTM, which is a low acetyl clarified grade of gellan gum, are viscous at low ionic strength but undergo a liquid- gel transition when the ionic strength is increased, and this is the case when this aqueous solution is introduced into the eye.
• the rigidity of the gel can be modified by adjusting the polymer concentration.
• the gellan gum product not only has the property of changing from the liquid to the gel phase when placed in a medium of higher ionic strength, but it also possesses the two advantageous additional properties of being thermoplastic and thixotropic which enable its fluidity to be increased by shaking or slightly warming the sample before administration. It will be appreciated that where gellan gum is used, the change from the liquid phase to the gel phase preferably occurs as a consequence of an increase in ionic strength due to the presence of mono- and divalent cations.
• the present invention relates to the ophthalmic compositions preferably containing about 0.1% to about 2.0% by weight of the polysaccharide described above, and about 0.01% to about 5% by weight of pilocarpine.
• the quantities relating to the aqueous gellan gum solution make it possible to obtain a suitable gel consistency and to compensate the loss induced by the sterilization procedures used during the process of manufacture of these ophthalmic compositions.
• the first component which is an acid aqueous solution of pilocarpine preferably has a pH in the range of 3.7-4.0.
• the second component which is an alkaline solution of a polysaccharide of the type which undergoes liquid-gel phase transition under the effect of an increase in the ionic strength preferably has a pH in the range of 9.0-9.5.
• additives can also take part in the ophthalmic compositions according to the invention.
• these are, in particular, other polymers suitable for topical application to the eye, small amounts of buffers, acids or bases for adjusting the pH to values suitable for administration to the eye, nonionic tonicity adjusting agents, agents for controlling bacterial contamination or any other additive which assist in the formulation.
• One particularly suitable preservative for use in the compositions of the present invention is benzododecinium bromide.
• mannitol can be used in the compositions according to the invention in order to regulate the tonicity of the medium without changing the gelling properties.
• Other tonicity adjusting agents can be used, sorbitol or any sugar for , xample.
• the ophthalmic compositions according to the invention are administered in liquid form, by a dual chamber vial such as a vial used for the ophthalmic product.
• a dual chamber vial such as a vial used for the ophthalmic product.
• TIMPILOTM see European Patent Specification No. 0 315 440-A.
• the compositions according to the invention can be administered in the usual manner for ophthalmic solutions, in the inferior cul-de-sac of the conjunctiva on the outside of the eye.
• a drop of liquid composition containing about 25mg of the ophthalmic composition enables about 0.0025mg to about 1.25mg of pilocarpine to be administered.
• pilocarpine may be used in the form of a pharmaceutically acceptable salt.
• Particularly preferred salts of pilocarpine are the nitrate and the hydrochloride salts.
• the tears produced by the eye dilute the active substance and very rapidly deplete the dose of active substance administered by conventional liquid solutions.
• compositions according to the invention containing a polysaccharide in aqueous solution of the type which undergoes liquid- el phase transition under the effect of an increase in the ionic strength are diluted less rapidly and make it possible to obtain a prolonged residence time which leads to more effective levels of concentration of active substance in the lacrimal film.
• compositions are instilled as viscous, non-gelled solutions which undergo liquid-gel phase transition in contact with the precorneal tear fluid, in order to improve the ocular penetration of the drug.
• each of these formulations is constituted by two solutions which have to be mixed before use:
• a pilocarpine nitrate concentrate at pH 3.70-4.00 This solution corrresponds to 25% of the final volume.
• a 0.8% Gelrite solution at pH 9.00-9.50 containing a tromethamine/maleic acid buffer and mannitol as isotonizing agent. This solution is a viscous liquid at room temperature and takes 75% of the final volume. It is to be added aseptically to the concentrate to reconstitute the eye drops at the time of dispensing. After mixing, the pH of the solution is in the range of 6.50 to 6.80. The reconstituted solutions are preserved with 0.012% benzododecinium bromide.
• the Pilocarpine/Gelrite formulations should be packaged m a dispensing system for packaging separately the two constituents which are mixed in sterile conditions extemporaneously at the time of first use of the system. Examples of such devices are described, for instance, in European patent specification Nos. 0 315 440-A and 0 417 998-A.
• the pH of the instilled solutions was the same for HEC and Gelrite solutions (close to 6.70).
• AUC (0-4 hrs) was increased by 2.1 in the aqueous humor and 4.9 in the iris + ciliary body
• Results obtained in the rabbit show a strong increase in the penetration properties of Pilocarpine when the drug is formulated in a Gelrite vehicle. The values are always higher at each point in the three ocular tissues, except in one experiment where they are similar.
• the ocular bioavailability of the Gelrite formulations is on average 2-fold higher than with an HEC vehicle.

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• 1997
  • 1997-03-12 JP JP9532296A patent/JP2000506182A/ja active Pending
  • 1997-03-12 EP EP97915364A patent/EP0893990A1/de not_active Withdrawn
  • 1997-03-12 AU AU22875/97A patent/AU2287597A/en not_active Abandoned
  • 1997-03-12 CA CA 2248881 patent/CA2248881A1/en not_active Abandoned
  • 1997-03-12 WO PCT/EP1997/001285 patent/WO1997033562A1/en not_active Application Discontinuation

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