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WO1997033562A1 - Composition ophtalmologique subissant une transition de phase liquide/gel - Google Patents

Composition ophtalmologique subissant une transition de phase liquide/gel Download PDF

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Publication number
WO1997033562A1
WO1997033562A1 PCT/EP1997/001285 EP9701285W WO9733562A1 WO 1997033562 A1 WO1997033562 A1 WO 1997033562A1 EP 9701285 W EP9701285 W EP 9701285W WO 9733562 A1 WO9733562 A1 WO 9733562A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
pilocarpine
polysaccharide
component
phase transition
Prior art date
Application number
PCT/EP1997/001285
Other languages
English (en)
Inventor
Gilles Chastaing
Annouk Rozier
Original Assignee
Laboratoires Merck Sharp & Dohme-Chibret Snc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from FR9603142A external-priority patent/FR2746014B1/fr
Application filed by Laboratoires Merck Sharp & Dohme-Chibret Snc filed Critical Laboratoires Merck Sharp & Dohme-Chibret Snc
Priority to AU22875/97A priority Critical patent/AU2287597A/en
Priority to EP97915364A priority patent/EP0893990A1/fr
Priority to JP9532296A priority patent/JP2000506182A/ja
Publication of WO1997033562A1 publication Critical patent/WO1997033562A1/fr

Links

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

Abstract

La présente invention se rapporte à une composition ophtalmologique destinée à être mise en contact avec le fluide lacrimal, à être administrée sous une forme liquide non gélifiée et à se gélifier in situ. Cette composition renferme au moins un polysaccharide dans une solution aqueuse et subit une transition de phase liquide-gel se gélifiant in situ sous l'effet d'une augmentation de la force ionique du fluide lacrimal. L'invention concerne également une substance pharmaceutiquement active telle que la pilocarpine ou un sel pharmaceutiquement acceptable de celle-ci. La composition comprend un premier composant qui est une solution aqueuse acide de policarpine et d'un second composant qui est une solution aqueuse neutre ou alcaline d'un polysaccharide qui subit la transition de phase liquide/gel sous l'effet d'une augmentation de la force ionique, ces composants étant mélangés extemporanément au moment de leur première utilisation.
PCT/EP1997/001285 1996-03-13 1997-03-12 Composition ophtalmologique subissant une transition de phase liquide/gel WO1997033562A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU22875/97A AU2287597A (en) 1996-03-13 1997-03-12 Ophthalmological composition of the type which undergoes liquid-gel phase tr ansition
EP97915364A EP0893990A1 (fr) 1996-03-13 1997-03-12 Composition ophtalmologique subissant une transition de phase liquide/gel
JP9532296A JP2000506182A (ja) 1996-03-13 1997-03-12 液―ゲル相転移を起こすタイプの点眼剤組成物

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US1334396P 1996-03-13 1996-03-13
FR96/03142 1996-03-13
US60/013,343 1996-03-13
FR9603142A FR2746014B1 (fr) 1996-03-13 1996-03-13 Composition ophtalmologique du type subissant une transition de phase liquide-gel

Publications (1)

Publication Number Publication Date
WO1997033562A1 true WO1997033562A1 (fr) 1997-09-18

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/001285 WO1997033562A1 (fr) 1996-03-13 1997-03-12 Composition ophtalmologique subissant une transition de phase liquide/gel

Country Status (5)

Country Link
EP (1) EP0893990A1 (fr)
JP (1) JP2000506182A (fr)
AU (1) AU2287597A (fr)
CA (1) CA2248881A1 (fr)
WO (1) WO1997033562A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001036000A1 (fr) * 1999-11-15 2001-05-25 Bio Syntech Canada, Inc. Solution biopolymere aqueuse auto-gelifiante en fonction du ph et a temperature controlee
GR20010100222A (el) * 2001-04-30 2002-12-19 Ηλιας Κ. Παπαδοπουλος Φαρμακευτικο παρασκευασμα για την διαγνωση και θεραπεια της στυτικης δυσλειτουργιας
US9867810B1 (en) 2016-08-19 2018-01-16 Orasis Pharmaceuticals Ltd. Ophthalmic pharmaceutical compositions and uses relating thereto
US11707436B2 (en) * 2014-12-15 2023-07-25 Nanosphere Health Sciences Inc. Methods of treating inflammatory disorders and global inflammation with compositions comprising phospholipid nanoparticle encapsulations of NSAIDS

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4725699B2 (ja) * 2002-04-08 2011-07-13 ライオン株式会社 眼科用組成物及び眼科用組成物配合用防腐剤
JP2010031052A (ja) * 2002-04-08 2010-02-12 Lion Corp 眼科用組成物、及び眼科製剤用防腐組成物

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0056420A1 (fr) * 1981-01-15 1982-07-28 Schering Corporation Gel ophtalmique
WO1994027578A1 (fr) * 1993-06-02 1994-12-08 Pharmacia Ab Gel a usage therapeutique in situ

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0056420A1 (fr) * 1981-01-15 1982-07-28 Schering Corporation Gel ophtalmique
WO1994027578A1 (fr) * 1993-06-02 1994-12-08 Pharmacia Ab Gel a usage therapeutique in situ

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001036000A1 (fr) * 1999-11-15 2001-05-25 Bio Syntech Canada, Inc. Solution biopolymere aqueuse auto-gelifiante en fonction du ph et a temperature controlee
US20100028434A1 (en) * 1999-11-15 2010-02-04 Bio Syntech Canada, Inc. Temperature controlled and pH dependent self gelling biopolymeric aqueous solution
US8920842B2 (en) * 1999-11-15 2014-12-30 Piramal Healthcare (Canada) Ltd. Temperature controlled and pH dependent self gelling biopolymeric aqueous solution
GR20010100222A (el) * 2001-04-30 2002-12-19 Ηλιας Κ. Παπαδοπουλος Φαρμακευτικο παρασκευασμα για την διαγνωση και θεραπεια της στυτικης δυσλειτουργιας
US11707436B2 (en) * 2014-12-15 2023-07-25 Nanosphere Health Sciences Inc. Methods of treating inflammatory disorders and global inflammation with compositions comprising phospholipid nanoparticle encapsulations of NSAIDS
US9867810B1 (en) 2016-08-19 2018-01-16 Orasis Pharmaceuticals Ltd. Ophthalmic pharmaceutical compositions and uses relating thereto
US10639297B2 (en) 2016-08-19 2020-05-05 Orasis Pharmaceuticals Ltd. Ophthalmic pharmaceutical compositions and uses relating thereto
US11129812B2 (en) 2016-08-19 2021-09-28 Orasis Pharmaceuticals Ltd. Ophthalmic pharmaceutical compositions and uses relating thereto
US11974986B2 (en) 2016-08-19 2024-05-07 Orasis Pharmaceuticals Ltd. Ophthalmic pharmaceutical compositions and uses relating thereto

Also Published As

Publication number Publication date
CA2248881A1 (fr) 1997-09-18
JP2000506182A (ja) 2000-05-23
EP0893990A1 (fr) 1999-02-03
AU2287597A (en) 1997-10-01

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