CA2248881A1 - Ophthalmological composition of the type which undergoes liquid-gel phase transition - Google Patents
Ophthalmological composition of the type which undergoes liquid-gel phase transition Download PDFInfo
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- CA2248881A1 CA2248881A1 CA 2248881 CA2248881A CA2248881A1 CA 2248881 A1 CA2248881 A1 CA 2248881A1 CA 2248881 CA2248881 CA 2248881 CA 2248881 A CA2248881 A CA 2248881A CA 2248881 A1 CA2248881 A1 CA 2248881A1
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- composition
- pilocarpine
- polysaccharide
- component
- phase transition
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- 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
Abstract
The present invention relates to an ophthalmological composition intended for contacting with the lacrimal fluid wherein 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.
Description
W O 97/33S62 PCT~EP97/01285 TITLE OF THE INVENTION
OPHTHALMOLOGICAL COMPOSITION OF THE TYPE WHICH
UNDERGOES LIQUID-GEL PHASE TRANSITION
The present invention relates to an ophthalmological composition cont~3ining 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.
A large percentage of drugs administered to the eye is lost as a result of lacrimal drainage; this applies especially in the case of a liquid formulation. In effect, as a result of this drainage, only a small fraction of the dose a~mini.qtered remains in contact with the cornea for a few 15 minutes, and an even smaller fraction penetrates into the eye.
To overcome this disadvantage, it is known to use viscous solutions, gels, eye ointments or solid eye implants.
Progress has been made in the delivery of drugs by the use of these galenical forms, especially by using the solid implants, by means of which 20 it is possible to reduce greatly the doses of active principle in the formulation while retaining a therapeutic response equivalent to that which would be induced by an ophth~lmi~ solution, the latter, in addition, needing to be administered more frequently.
~ome of these implants function by diffusion. Thus, for example, in 25 the "OCUSERTTM" system, one weekly application of an oval lens in the conjunctival sac enables an active principle to be delivered by diffusion, ~ but this lens has to be removed after use, which is a source of problems for the patients.
Others function by dissolution, and, in this case, since the implants 30 are either soluble or autodegradable ("LACRISERTTM" system), their duration of action is much shorter.
W O 97/33562 rCT~EP97/0128S
OPHTHALMOLOGICAL COMPOSITION OF THE TYPE WHICH
UNDERGOES LIQUID-GEL PHASE TRANSITION
The present invention relates to an ophthalmological composition cont~3ining 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.
A large percentage of drugs administered to the eye is lost as a result of lacrimal drainage; this applies especially in the case of a liquid formulation. In effect, as a result of this drainage, only a small fraction of the dose a~mini.qtered remains in contact with the cornea for a few 15 minutes, and an even smaller fraction penetrates into the eye.
To overcome this disadvantage, it is known to use viscous solutions, gels, eye ointments or solid eye implants.
Progress has been made in the delivery of drugs by the use of these galenical forms, especially by using the solid implants, by means of which 20 it is possible to reduce greatly the doses of active principle in the formulation while retaining a therapeutic response equivalent to that which would be induced by an ophth~lmi~ solution, the latter, in addition, needing to be administered more frequently.
~ome of these implants function by diffusion. Thus, for example, in 25 the "OCUSERTTM" system, one weekly application of an oval lens in the conjunctival sac enables an active principle to be delivered by diffusion, ~ but this lens has to be removed after use, which is a source of problems for the patients.
Others function by dissolution, and, in this case, since the implants 30 are either soluble or autodegradable ("LACRISERTTM" system), their duration of action is much shorter.
W O 97/33562 rCT~EP97/0128S
In all cases, the solid implants possess a major disadvantage in that many patients find it difficult to tolerate the introduction into the conjunctival cul-de-sacs of the solid object represented by this implant.
To solve this problem, 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".
These "PLURONICTM polyols" are thermally gelling polymers in which the polymer concentration is chosen in accordance with the desired liquid-gel transition temperature. Howe~er, with the commercially available "PLURONICTM polyols", it is difficult to obtain a gel of suitable rigidity while maintaining the transition temperature at physiological temperatures.
Similarly, Canadian Patent 1,072,413 describes systems where the gelification temperatures are made higher than room temperature by using additives.
The thermally gelling systems have many disadvantages, including the risk of gelling before a~mini.stration by an increase in the ambient temperature during park~3ging 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 wll;ch undergo liquid-gel phase transition gelling i77, situ under the effect ofan 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.
WO 97/33S62 PCT/EE~97/01285 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 5Ø The recommended dosage regimen of such - 5 formulations is one to two drops, two to four times a day. In an attempt to provide a sustained release formulation, 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. However, gels are difficult to apply and can cause blurred vision. For these reasons, they are less well accepted by patients than solutions.
Whilst the stability of pilocarpine is optimum in aqueous acid solution, the ocular bioavailability and tolerance of the drug are far better at approximately neutral pH. In view of these properties, freeze-dried formulations of pilocarpine which require reconstitution by the patient l 5 prior to use have been developed. The pH of the reconstituted formulations is 6.5-6.7. Such formulations, however, suffer from the drawbacks of the necessity for non-sterile reconstitution by the patient.
No dual chamber ophth~lmic vial exists for freeze-dried products.
Furthermore, due to incompatibility of gellan gum at low pH, pilocarpine cannot be formulated in the manner described in European Patent Specification No. 0 227 494-A as a ready-to-use gellan gum solution.
More recently, a comparison of the ocular penetration of pilocarpine following bilateral instillation of either 1% pilocarpine in 0.6% GelriteTM or 1% Chibro-PilocarpineTM (cont~ining 0.325% hydroxyethyl cellulose) has been reported (Inuestigative Ophthalmology & Visual Scie1lce, 15 March 1995, Vol. 36, No. 4, S159). The study concludes that the gelling polymer GelriteTM increases ocular drug bioavailability, but gives no details of the pilocarpine/GelriteTM formulation.
The present invention relates to an ophthalmological composition intended for contacting with the lacrimal fluid where said composition is intended to be arlmini~tered as a non-gelled liquid form and is intended to gel i7~ situ, this composition cont~ining 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 5 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 z~lk~line aqueous 10 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.
The composition of the present invention, which takes the form of a liquid before its introduction into the eye, undergoes a liquid-gel phase 15 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. In particular, since the presence of lacrimal fluid is 20 required to induce gel formation, any accidental spillage of solution outside of the eye cannot result in gel formation. Furthermore, in contrast to the thermally gelling systems, an increase in the ambient temperature cannot result in the solution gelling during storage.
Also, the polymer used can form a gel at concentrations 10- to 100-25 fold lower than those used in systems involving thermogelification. It ishence very well tolerated by the eye.
Following misrin~ of the two components of the composition, 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 30 bioavailability and tolerance of pilocarpine. The bioavailability is furthe enhanced by the presence of the polysaccharide. Therefore, the compositions of the present invention which are a~mini.~tered 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.
S 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.
The compositions according to the invention have, on the one hand, the advantage of liquid ophth~lmic 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.
The 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.
The aqueous polysaccharide solutions, of the 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.
Thus, according to the invention, an extracellular anionic heteropolysaccharide elaborated by the bacterium Pseudomo1las elodea and known by the name gellan gum is preferably used.
This polysaccharide, manufactured by Monsanto Performance Materials, is already used as a gelling agent for pharmaceutical compositions, for culture media and also in food products. The structure of this heteropolysaccharide consists of the following tetrasaccharide repeating unit:
WO 97/33562 PCT/~i:P97/01285 ~3)~ D-Glcp-(1~4)-~-D-GlcpA-(1~4)-~-D-Glcp-(1~4)-a-L-Rhap-(1~
which may, or may not, be partially O-acetylated on its ~-D-glucopyranose (,B-D-Glcp) residues.
S The preparation of such polysaccharides in native and deacetylated form is described, in particular, in US Patent Nos. 4,326,053 and 4,326,052 of Merck & Co., Inc. Rahway N.J., and their structure has been described, in particular, by Jansson & Lindberg, Carbohydr. Res. 124 (1983) 135-139.
According to the present invention, aqueous solutions cont~ining 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 cl~nging 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 ar~lnini.~tration. It will be appreciated that where gellan gum is used, the change from the liquid phase to the gel phase preferably OCCUl'S as a consequence of an increase in ionic strength due to the presence of mono-and divalent cations.
Applicants have demonstrated gel formation in a rabbit's eye following a 20~1 instillation of a solution cont~ining 0.4% by weight of GelriteTM in deionized water.
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 5 induced by the sterilization procedures used during the process of manufacture of these ophth~lmi~ compositions.
In the ophthalmological compositions of the present invention, the first component which is an acid aqueous solution of pilocarpine preferably has a pH in the range of 3.7-4Ø
The second component which is an ~lk~line 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 p~I in the range of 9.0-9.5.
Other additives can also take part in the opht.h~lnnir 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 a~mini.~tration 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.
As will emerge in the examples, mannitol can be used in the compositions according to the invention in order to regulate the tonicity of the medium without ch~nging the gelling properties.
Other tonicity adjusting agents can be used, sorbitol or any sugar fo], ~xample.
For their administration to the eye, 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 TIMPILOTM
(see European Patent Specification No. 0 316 440-A).
The compositions according to the invention can be arimini.~tered in the usual manner for ophth~lmic solutions, in the inferior cul-de-sac of the conjunctiva on the outside of the eye.
By way of example, a drop of liquid composition cont~ining about 25mg of the ophth~lmi~ composition enables about 0.0025mg to about 1.2~mg of pilocarpine to be administered.
Toxicological studies prove the good tolerability of gellan gums:
acute oral toxicity tests in rats show that the lethal dose 50 (LDso) is greater than 5000mg per kg; acute toxicity tests by inhalation show that exposure of rats for 4 hours to a nominal concentration of 6.09mg/l does not cause the death of any ~nim~l in a group of 10 ~nim~l~, which indicates that the lethal concentration 50 (LCso) is greater than 6.09mg/l.
DRAIZE-type eye irritation tests in rabbits show that the product is not regarded as an eye irritant.
l 5 In the compositions of the present invention, pilocarpine may be used in the form of a pharmaceutically acceptable salt. Particularly preferred salts of pilocarpine are the nitrate and the hydrochloride salts.
Generally, the tears produced by the eye dilute the active substance and very rapidly deplete the dose of active substance administered by conventional liquid solutions.
The compositions according to the invention cont~ining a polysaccharide in aqueous solution of the type which undergoes liquid-gel 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.
The characteristics and advantages of compositions of the present invention are illustrated by the following Examples:
FORMULATION
1% and 2% pilocarpine nitrate are formulated in 0.6% Gelrite Ophthalmic Solution (Tables 1 and 2). In these conditions, the S 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.
Due to the poor stability of the pilocarpine at neutral pH, 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, cont~ining 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.
It has to be noted that the respective proportions of the concentrate to the diluent are the best compromise between the solubilitv of the pilocarpine nitl ate in the concentrate and the viscosity of the Gelrite diluent.
Table 1: 1% PilocarPine Nitrate/Gelrite Ophthalmic Solution Component Active Concentrate ~ Pilocarpine Nitrate, USP 40 mg ~ Water for Injection, USP qs 1.00 g Gelrite Diluent ~ Gelrite (anhydrous) 8.00 mg ~ Mannitol, USP 45.33 mg ~ Tromet.h.qmine, USP 2.40 mg ~ MaleicAcid, BP 0.40 mg ~ Benzododecinium Bromide (anhydrous) 0.16 mg ~ Water for Injection, USP qs 1.00 g Reconstituted Sol. *
~ Pilocarpine Nitrate, USP 10.00 mg ~ Gelrite (anhydrous) 6.00 mg ~ Mannitol, USP 34.00 mg ~ Tromethamine, USP 1.80 mg ~ Maleic Acid, BP 0.30 mg ~ Benzododecinium Bromide (anhydrous) 0.12 mg ~ Water for Injection, USP qs 1.00 g * Based Ol1 final volume of 10.0ml (2.5ml of concentrate plus 7.~ml of diluent).
Table 2: 2% PilocarPine Nitrate/Gelrite Ophthalmic Solution Component Active Concentrate ~ Pilocarpine Nitrate, USP 80 mg ~ Water for Injection, USP qs 1.00 g Gelrite Diluent ~ Gelrite (anhydrous) 8.00 mg ~ Mannitol, USP 29.30 mg ~ Trometh~mine, USP 3.00 mg ~ Benzododecinium Bromide (anhydrous) 0.16 mg ~ Waterfor Injection, USP qs 1.00 g Reconstituted Sol. *
~ Pilocarpine Nitrate, USP 20.00 mg ~ Gelrite (anhydrous) 6.00 mg ~ Mannitol, USP 22.00 mg ~ Tromethamine, USP 2.25 mg ~ Benzododecinium Bromide (anhydrous) 0.12 mg ~ Water for Injection, USP qs 1.00 g * Based on final volume of 10.0ml (2.5ml of concentrate plus 7.5ml of S diluent).
PACKAGING PROCESS
~ The Pilocarpine/Gelrite formulations should be packaged in 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.
OCULAR PENETRATION
The 1% and 2% Pilocarpine/Gelrite Ophthalmic Solutions were tested in ocular distribution studies in the rabbit and compared with the corresponding 0.325% hydroxyethylcellulose (H~C) marketed solutions (Chibro-PilocarpineTM 1% and 2%).
The pH of the instilled solutions was the same for HEC and Gelrite solutions (close to 6.70).
1/ 1% Pilocarpine Ophthalmic Solutions The solutions were tested in the albino and pigmented rabbits:
a. Albino Rabbit Penetrations in the cornea were the same for the Gelrite and HEC
vehicles, but were signifcantly higher (p ' 0.05) at each time point in the aqueous humor and iris + ciliary body for the Gelrite formulations. Ocular bioavailability measured by calculations of the AUC (0-4 hrs) was increased by 2.1 in the aqueous humor and 4.9 in the iris + ciliary body.
b. Pi~mented Rabbit Mean Pilocarpine concentrations in cornea, aqueous humor and il'iS +
ciliary body were higher at each time point with Gelrite than with -WO 97/33562 PCT/EI'97/01285 Chibro-PilocarpineTM 1%. Ocular bioavailability (AUCs) was increased in the cornea, aqueous humor and iris + ciliary body by 2.0, 2.6 and 1.6, respectively, in favour of the Gelrite formulation.
5 2/ 2% Pilocarpine Ophthalmic Solutions The two solutions were tested in the albino rabbit:
Mean Pilocarpine concentrations in each tissue were always higher with the Gelrite formulation than with Chibro-PilocarpineTM 2%. AUCs (0-4hrs) were increased in the cornea, aqueous humor and iris + ciliary body by 2.4, 2.0 and 2.3, respectively, in favour of the Gelrite formulation.
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 .~imil~r.
Based on these data, the ocular bioavailability of the Gelrite formulations is on average 2-fold higher than with an HEC vehicle.
To solve this problem, 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".
These "PLURONICTM polyols" are thermally gelling polymers in which the polymer concentration is chosen in accordance with the desired liquid-gel transition temperature. Howe~er, with the commercially available "PLURONICTM polyols", it is difficult to obtain a gel of suitable rigidity while maintaining the transition temperature at physiological temperatures.
Similarly, Canadian Patent 1,072,413 describes systems where the gelification temperatures are made higher than room temperature by using additives.
The thermally gelling systems have many disadvantages, including the risk of gelling before a~mini.stration by an increase in the ambient temperature during park~3ging 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 wll;ch undergo liquid-gel phase transition gelling i77, situ under the effect ofan 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.
WO 97/33S62 PCT/EE~97/01285 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 5Ø The recommended dosage regimen of such - 5 formulations is one to two drops, two to four times a day. In an attempt to provide a sustained release formulation, 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. However, gels are difficult to apply and can cause blurred vision. For these reasons, they are less well accepted by patients than solutions.
Whilst the stability of pilocarpine is optimum in aqueous acid solution, the ocular bioavailability and tolerance of the drug are far better at approximately neutral pH. In view of these properties, freeze-dried formulations of pilocarpine which require reconstitution by the patient l 5 prior to use have been developed. The pH of the reconstituted formulations is 6.5-6.7. Such formulations, however, suffer from the drawbacks of the necessity for non-sterile reconstitution by the patient.
No dual chamber ophth~lmic vial exists for freeze-dried products.
Furthermore, due to incompatibility of gellan gum at low pH, pilocarpine cannot be formulated in the manner described in European Patent Specification No. 0 227 494-A as a ready-to-use gellan gum solution.
More recently, a comparison of the ocular penetration of pilocarpine following bilateral instillation of either 1% pilocarpine in 0.6% GelriteTM or 1% Chibro-PilocarpineTM (cont~ining 0.325% hydroxyethyl cellulose) has been reported (Inuestigative Ophthalmology & Visual Scie1lce, 15 March 1995, Vol. 36, No. 4, S159). The study concludes that the gelling polymer GelriteTM increases ocular drug bioavailability, but gives no details of the pilocarpine/GelriteTM formulation.
The present invention relates to an ophthalmological composition intended for contacting with the lacrimal fluid where said composition is intended to be arlmini~tered as a non-gelled liquid form and is intended to gel i7~ situ, this composition cont~ining 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 5 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 z~lk~line aqueous 10 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.
The composition of the present invention, which takes the form of a liquid before its introduction into the eye, undergoes a liquid-gel phase 15 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. In particular, since the presence of lacrimal fluid is 20 required to induce gel formation, any accidental spillage of solution outside of the eye cannot result in gel formation. Furthermore, in contrast to the thermally gelling systems, an increase in the ambient temperature cannot result in the solution gelling during storage.
Also, the polymer used can form a gel at concentrations 10- to 100-25 fold lower than those used in systems involving thermogelification. It ishence very well tolerated by the eye.
Following misrin~ of the two components of the composition, 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 30 bioavailability and tolerance of pilocarpine. The bioavailability is furthe enhanced by the presence of the polysaccharide. Therefore, the compositions of the present invention which are a~mini.~tered 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.
S 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.
The compositions according to the invention have, on the one hand, the advantage of liquid ophth~lmic 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.
The 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.
The aqueous polysaccharide solutions, of the 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.
Thus, according to the invention, an extracellular anionic heteropolysaccharide elaborated by the bacterium Pseudomo1las elodea and known by the name gellan gum is preferably used.
This polysaccharide, manufactured by Monsanto Performance Materials, is already used as a gelling agent for pharmaceutical compositions, for culture media and also in food products. The structure of this heteropolysaccharide consists of the following tetrasaccharide repeating unit:
WO 97/33562 PCT/~i:P97/01285 ~3)~ D-Glcp-(1~4)-~-D-GlcpA-(1~4)-~-D-Glcp-(1~4)-a-L-Rhap-(1~
which may, or may not, be partially O-acetylated on its ~-D-glucopyranose (,B-D-Glcp) residues.
S The preparation of such polysaccharides in native and deacetylated form is described, in particular, in US Patent Nos. 4,326,053 and 4,326,052 of Merck & Co., Inc. Rahway N.J., and their structure has been described, in particular, by Jansson & Lindberg, Carbohydr. Res. 124 (1983) 135-139.
According to the present invention, aqueous solutions cont~ining 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 cl~nging 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 ar~lnini.~tration. It will be appreciated that where gellan gum is used, the change from the liquid phase to the gel phase preferably OCCUl'S as a consequence of an increase in ionic strength due to the presence of mono-and divalent cations.
Applicants have demonstrated gel formation in a rabbit's eye following a 20~1 instillation of a solution cont~ining 0.4% by weight of GelriteTM in deionized water.
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 5 induced by the sterilization procedures used during the process of manufacture of these ophth~lmi~ compositions.
In the ophthalmological compositions of the present invention, the first component which is an acid aqueous solution of pilocarpine preferably has a pH in the range of 3.7-4Ø
The second component which is an ~lk~line 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 p~I in the range of 9.0-9.5.
Other additives can also take part in the opht.h~lnnir 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 a~mini.~tration 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.
As will emerge in the examples, mannitol can be used in the compositions according to the invention in order to regulate the tonicity of the medium without ch~nging the gelling properties.
Other tonicity adjusting agents can be used, sorbitol or any sugar fo], ~xample.
For their administration to the eye, 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 TIMPILOTM
(see European Patent Specification No. 0 316 440-A).
The compositions according to the invention can be arimini.~tered in the usual manner for ophth~lmic solutions, in the inferior cul-de-sac of the conjunctiva on the outside of the eye.
By way of example, a drop of liquid composition cont~ining about 25mg of the ophth~lmi~ composition enables about 0.0025mg to about 1.2~mg of pilocarpine to be administered.
Toxicological studies prove the good tolerability of gellan gums:
acute oral toxicity tests in rats show that the lethal dose 50 (LDso) is greater than 5000mg per kg; acute toxicity tests by inhalation show that exposure of rats for 4 hours to a nominal concentration of 6.09mg/l does not cause the death of any ~nim~l in a group of 10 ~nim~l~, which indicates that the lethal concentration 50 (LCso) is greater than 6.09mg/l.
DRAIZE-type eye irritation tests in rabbits show that the product is not regarded as an eye irritant.
l 5 In the compositions of the present invention, pilocarpine may be used in the form of a pharmaceutically acceptable salt. Particularly preferred salts of pilocarpine are the nitrate and the hydrochloride salts.
Generally, the tears produced by the eye dilute the active substance and very rapidly deplete the dose of active substance administered by conventional liquid solutions.
The compositions according to the invention cont~ining a polysaccharide in aqueous solution of the type which undergoes liquid-gel 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.
The characteristics and advantages of compositions of the present invention are illustrated by the following Examples:
FORMULATION
1% and 2% pilocarpine nitrate are formulated in 0.6% Gelrite Ophthalmic Solution (Tables 1 and 2). In these conditions, the S 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.
Due to the poor stability of the pilocarpine at neutral pH, 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, cont~ining 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.
It has to be noted that the respective proportions of the concentrate to the diluent are the best compromise between the solubilitv of the pilocarpine nitl ate in the concentrate and the viscosity of the Gelrite diluent.
Table 1: 1% PilocarPine Nitrate/Gelrite Ophthalmic Solution Component Active Concentrate ~ Pilocarpine Nitrate, USP 40 mg ~ Water for Injection, USP qs 1.00 g Gelrite Diluent ~ Gelrite (anhydrous) 8.00 mg ~ Mannitol, USP 45.33 mg ~ Tromet.h.qmine, USP 2.40 mg ~ MaleicAcid, BP 0.40 mg ~ Benzododecinium Bromide (anhydrous) 0.16 mg ~ Water for Injection, USP qs 1.00 g Reconstituted Sol. *
~ Pilocarpine Nitrate, USP 10.00 mg ~ Gelrite (anhydrous) 6.00 mg ~ Mannitol, USP 34.00 mg ~ Tromethamine, USP 1.80 mg ~ Maleic Acid, BP 0.30 mg ~ Benzododecinium Bromide (anhydrous) 0.12 mg ~ Water for Injection, USP qs 1.00 g * Based Ol1 final volume of 10.0ml (2.5ml of concentrate plus 7.~ml of diluent).
Table 2: 2% PilocarPine Nitrate/Gelrite Ophthalmic Solution Component Active Concentrate ~ Pilocarpine Nitrate, USP 80 mg ~ Water for Injection, USP qs 1.00 g Gelrite Diluent ~ Gelrite (anhydrous) 8.00 mg ~ Mannitol, USP 29.30 mg ~ Trometh~mine, USP 3.00 mg ~ Benzododecinium Bromide (anhydrous) 0.16 mg ~ Waterfor Injection, USP qs 1.00 g Reconstituted Sol. *
~ Pilocarpine Nitrate, USP 20.00 mg ~ Gelrite (anhydrous) 6.00 mg ~ Mannitol, USP 22.00 mg ~ Tromethamine, USP 2.25 mg ~ Benzododecinium Bromide (anhydrous) 0.12 mg ~ Water for Injection, USP qs 1.00 g * Based on final volume of 10.0ml (2.5ml of concentrate plus 7.5ml of S diluent).
PACKAGING PROCESS
~ The Pilocarpine/Gelrite formulations should be packaged in 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.
OCULAR PENETRATION
The 1% and 2% Pilocarpine/Gelrite Ophthalmic Solutions were tested in ocular distribution studies in the rabbit and compared with the corresponding 0.325% hydroxyethylcellulose (H~C) marketed solutions (Chibro-PilocarpineTM 1% and 2%).
The pH of the instilled solutions was the same for HEC and Gelrite solutions (close to 6.70).
1/ 1% Pilocarpine Ophthalmic Solutions The solutions were tested in the albino and pigmented rabbits:
a. Albino Rabbit Penetrations in the cornea were the same for the Gelrite and HEC
vehicles, but were signifcantly higher (p ' 0.05) at each time point in the aqueous humor and iris + ciliary body for the Gelrite formulations. Ocular bioavailability measured by calculations of the AUC (0-4 hrs) was increased by 2.1 in the aqueous humor and 4.9 in the iris + ciliary body.
b. Pi~mented Rabbit Mean Pilocarpine concentrations in cornea, aqueous humor and il'iS +
ciliary body were higher at each time point with Gelrite than with -WO 97/33562 PCT/EI'97/01285 Chibro-PilocarpineTM 1%. Ocular bioavailability (AUCs) was increased in the cornea, aqueous humor and iris + ciliary body by 2.0, 2.6 and 1.6, respectively, in favour of the Gelrite formulation.
5 2/ 2% Pilocarpine Ophthalmic Solutions The two solutions were tested in the albino rabbit:
Mean Pilocarpine concentrations in each tissue were always higher with the Gelrite formulation than with Chibro-PilocarpineTM 2%. AUCs (0-4hrs) were increased in the cornea, aqueous humor and iris + ciliary body by 2.4, 2.0 and 2.3, respectively, in favour of the Gelrite formulation.
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 .~imil~r.
Based on these data, the ocular bioavailability of the Gelrite formulations is on average 2-fold higher than with an HEC vehicle.
Claims (15)
1. 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.
2. A composition as claimed in claim 1 in which the polysaccharide is obtained by fermentation of a microorganism.
3. A composition as claimed in claim 2, in which the microorganism is Pseudomonas elodea.
4. A composition as claimed in claim 1, in which the polysaccharide has as its basic tetrasaccharide repeating unit:
~3)-.beta.-D-Glep-(1~4)-.beta.-D-GlepA-(1~4)-.beta.-D-Glep-(1~4)-.alpha.-L-Rhap-(1~
which may, or may not, be partially O-acetylated on its .beta.-D-glucopyranose (.beta.-D-Glep) residues.
~3)-.beta.-D-Glep-(1~4)-.beta.-D-GlepA-(1~4)-.beta.-D-Glep-(1~4)-.alpha.-L-Rhap-(1~
which may, or may not, be partially O-acetylated on its .beta.-D-glucopyranose (.beta.-D-Glep) residues.
5. A composition as claimed in claim 1, which contains about 0.1% to about 2.0% by weight of the said polysaccharide.
6. A composition as claimed in claim 1, which contains 0.01% to about 5% by weight of pilocarpine.
7. A composition as claimed in claim 6, which contains 1% or 2%
of pilocarpine.
of pilocarpine.
8. A composition as claimed in claim 1, in which the first component which is an acid aqueous solution of pilocarpine has a pH in the range of 3.7-4Ø
9. A composition as claimed in claim 1, in which 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 has a pH in the range of 9.0-9.5.
10. A composition as claimed in claim 1, in which, following mixing of the two components of the composition, the formulation has a pH in the range of 6.5-6.8.
11. A composition as claimed in claim 1 which contains in addition one or more other additives selected from other polymers suitable for topical application to the eye, buffers, acids or bases for adjusting the pH to values suitable for administration to the eye, nonionic tonicity adjusting agents, or agents for controlling bacterial contamination.
12. A composition as claimed in claim 11, in which the agent for controlling bacterial contamination is benzododecinium bromide.
13. A composition as claimed in claim 11, in which the tonicity adjusting agent is mannitol or sorbitol.
14. A composition as claimed in claim 1 in which the first component is a pilocarpine nitrate or pilocarpine hydrochloride concentrate at pH 3.70-4.00.
15. A composition as claimed in claim 1, in which the second component is a Gelrite TM solution at pH 9.00-9.50, containing a tromethamine or tromethamine/maleic acid buffer and mannitol.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1334396P | 1996-03-13 | 1996-03-13 | |
| FR9603142A FR2746014B1 (en) | 1996-03-13 | 1996-03-13 | LIQUID-GEL PHASE TRANSITION TYPE OPHTHALMOLOGICAL COMPOSITION |
| US60/013,343 | 1996-03-13 | ||
| FR9603142 | 1996-03-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2248881A1 true CA2248881A1 (en) | 1997-09-18 |
Family
ID=26232584
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2248881 Abandoned CA2248881A1 (en) | 1996-03-13 | 1997-03-12 | Ophthalmological composition of the type which undergoes liquid-gel phase transition |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0893990A1 (en) |
| JP (1) | JP2000506182A (en) |
| AU (1) | AU2287597A (en) |
| CA (1) | CA2248881A1 (en) |
| WO (1) | WO1997033562A1 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK1229940T3 (en) * | 1999-11-15 | 2014-08-18 | Piramal Healthcare Canada Ltd | TEMPERATURE CONTROL AND PH-DEPENDENT SELF-GELING, Aqueous BIOPOLYMER SOLUTION |
| GR1004266B (en) * | 2001-04-30 | 2003-06-18 | Ηλιας Κ. Παπαδοπουλος | Pharmaceutical concoction for the diagnosis and therapy of erection problems |
| JP2010031052A (en) * | 2002-04-08 | 2010-02-12 | Lion Corp | Composition for ophthalmic use and antiseptic composition for ophthalmology preparation |
| JP4725699B2 (en) * | 2002-04-08 | 2011-07-13 | ライオン株式会社 | Ophthalmic composition and preservative for blending ophthalmic composition |
| 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 |
| PT3500255T (en) | 2016-08-19 | 2023-01-10 | Orasis Pharmaceuticals Ltd | Ophthalmic pharmaceutical compositions and uses relating thereto |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0056420A1 (en) * | 1981-01-15 | 1982-07-28 | Schering Corporation | Ophthalmic gel |
| SE9301877D0 (en) * | 1993-06-02 | 1993-06-02 | Kabi Pharmacia Ab | IN SITU GEL FOR THERAPEUTIC USE |
-
1997
- 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
- 1997-03-12 JP JP9532296A patent/JP2000506182A/en active Pending
- 1997-03-12 AU AU22875/97A patent/AU2287597A/en not_active Abandoned
- 1997-03-12 EP EP97915364A patent/EP0893990A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| JP2000506182A (en) | 2000-05-23 |
| WO1997033562A1 (en) | 1997-09-18 |
| EP0893990A1 (en) | 1999-02-03 |
| AU2287597A (en) | 1997-10-01 |
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