CA1280367C - Pharmaceutical composition of the type which undergoes liquid-gel phase transition - Google Patents
Pharmaceutical composition of the type which undergoes liquid-gel phase transitionInfo
- Publication number
- CA1280367C CA1280367C CA000519753A CA519753A CA1280367C CA 1280367 C CA1280367 C CA 1280367C CA 000519753 A CA000519753 A CA 000519753A CA 519753 A CA519753 A CA 519753A CA 1280367 C CA1280367 C CA 1280367C
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- CA
- Canada
- Prior art keywords
- composition
- active substance
- pharmaceutically active
- liquid
- polysaccharide
- Prior art date
- Legal status (The legal status 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 status listed.)
- Expired - Lifetime
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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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/04—Polysaccharides, i.e. compounds containing more than five saccharide radicals attached to each other by glycosidic bonds
-
- 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
-
- 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
Abstract
TITLE OF THE INVENTION
PHARMACEUTICAL COMPOSITION OF THE TYPE WHICH
UNDERGOES LIQUID-GEL PHASE TRANSITION
ABSTRACT OF THE DISCLOSURE
The present invention relates to a pharma-ceutical composition intended for contacting with a physiological liquid characterized in that said compo-sition 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 physiological liquid.
PHARMACEUTICAL COMPOSITION OF THE TYPE WHICH
UNDERGOES LIQUID-GEL PHASE TRANSITION
ABSTRACT OF THE DISCLOSURE
The present invention relates to a pharma-ceutical composition intended for contacting with a physiological liquid characterized in that said compo-sition 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 physiological liquid.
Description
~8~36~ 17277 The present invention relates to a ph~rmaceu-tical composition containing at least one polysaccha-ride in aqueous solution, of the type which undergoes liquid-gel phase transition under the effect of an increase in the ionic strength.
The pharmaceutical compositions of the invention are of the type which undergoes liquid-gel phase tran-sition under the effect of an increase in the ionic strength.
They are particularly intended for contacting with physiological liquids. Thus the transition occurs at the contact, as the physiological liquids have a higher tonicity than the one of said compositions.
The compositions of the invention are specially useful for ophtalmic use, but also as injectable form, the formed gel having thus the function of slow-release form, as by intradermic or intramuscular injections, or as galenic form intended for contacting with mucous membranes.
~2~36~ 17277 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 efect, as a result of this drainage, only a small ~raction of the dose administered rémains in contact with the cornea for a ~ew 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 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 eye lotion, the latter, in addition, needing to be administered more ~requently.
Some oftheseimplants function by diffusion. Thus, for example, in the "OCUSERT ~ " system, one weekly appli-cation 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 pro-blems ~or the patients.
Others ~unction by dissolution, and, in this case, since the implants are either soluble or autodegradable ("LACRISERT ~ " system), their duration of action is much shorter.
In all cases, the solid implants possess a major disadvantage in that many patients find it difficult to tolerate the introduction into the conjunctival culs-de-sacs of the solid object represented by this implant.
To solve this problem, galenical forms can be usedwhich are liquid at room temperature and assure a semi-solid form at human body temperature. Such delivery systems ~ 7 17277 are described in US Patent 4,188,373, which propose the use of "PLURONIC ~ polyols".
These "PLURONIC ~ polyols" are thermally gelling polymers in which the polymer concentration ~s chosen in accordance with the desired liquid-gel transltion tempera-ture.
However, with the commercially available "PLUR~NIC
polymers", it is difficult to obtain a gel of suitable rigi-dity while maintaining the transition temperature at physio-logical temperatures, which are of the order: of 25 C -Similarly, Canadian Patent 1,072,413 describes sys-tems containing a therapeutic or other agent (poloxamer), the gelification temperatures of which are made higher than room temperature by using additives.
The thermally gelling systems have many disadvanta-ges, including the risk of gelling before administration by an increase in the ambient te~;perature during packaging or storage, for example.
US Patent 4,474,751 of ~Ierck & Co., relates to other systems for delivering drugs based on thermogelifica-tion of gels, but these systems require very large amounts of polymers and this is not always well tolerated by the eye.
The present invention relates to a pharmaceutical composition intended for contacting with a physiological liquid characterized in that said composition is intended to be administered as a non-gelled liquid form and is inten-ded to gel in situ, this composition containing at least one polysaccharide in aqueous solution, of the type which under-goes liquid-gel phase transition gelling in situ under the effect of an increase in the ionic strength of said physio-logical liquid.
The prefered pharmaceutical composition according ~ 6 ~ 17277 to the invention is an ophthalmological composition, the physiological liquide being the lacrimalfluid. mus, the pre-sent invention overcomes these particular problems of ad-ministering ophthalmic compositions.
As a matter of fact, the composition, 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 introdu-ced into the eye, as a result of the ionic strength of the physiological fluid which is in this case, the lacrimal fluid.
This new ophthalmological composition is an amaz-ingly advantageous form for several reasons. In particular, since the presence of lacrimal fluid is 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 gel-ling during storage.
Also, the polymer used can form a gel at concentra-tions lO- to lO0- fold lower than those used in systems in-volving thermogelification. It is hence very well tolera-ted by the eye.
Finally, when these compositions contain a pharma-ceutically active substance, such a delivery system makes it possible to achieve great bioavailability of the product, and concentrations of active principle which are sustained with time, advantages of a slow delivery system.
Furthermore, in the case of already gelled or semi-solid compositions, it is not possible to administer themby volumetric means, especially when they come from a multi-dose container. To administer these in reproducihle quantities, one is then com elled to employ gravimetric ~8~3~ 7 17277 means.
The compositions according to the invention have, on the one hand, the advantage of liquid ophthalmic compo-sitions, namely reproducible and accurate dosing, by volu-metric means, of the active substance, and on the otherhand the advantages known for the systems in rigid or semi solid gel form, relating to the delivery of active sub-stances.
The composition according to the invention conse-quently has neither the disadvantages of losses of activesubstances 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 Applicant Company has demonstrated that aqueous polysaccharide solutions, of the type which undergoes liquid-gel phase transition under the effect o~ an increase in the ionic strength, and are especially suitable accor-ding to the invention, are solutions of a polysaccharide obtained by fermentation of a microorganism.
Thus, acccrding to the invention, an extracellular anionic heteropolysaccharide elaborated by the bacterium Pseudomonas elodea and known by the name gellan gum is preferably used.
This polysaccharide, manufactured by KELCO & CO., is already used as a gelling agent for culture medium and also in food products. The structure of this heteropolysac-charide consists of the following tetrasaccharide repeating unit :
- 3)-~LD-Glcp-(l~4,-~LD-GlcpA-(l~4)-~-D-Glcp-(l~4)-~-L Rhap-(l~
which may, or may not, be partially C-acetylated on its ~-D-glucopyranose ~-D-Glcp) residues.
-~ 6 ~ 17277 The preparation of such polysaccharides in native and deacetylated form is described, in particular, in Patents US 4,326,053 and 4,326,052 of MERCK & CO., Inc. ~ahway N.~., and their structure has been described, in particular, b~
JANSSON & LINDBERG, Carbohydr. res. 124 (1983) 135-9.
Accordiny to the present invention, aqueous solu~
tions containing about O.l ~ to about 2.0 ~ by weight of gellan gum, and especially of the product known by the tra-dename Gelrite ~ , which is a low acetyl clarified grade of gellan gum, are viscous at low ionic strength but under-go a liquid-gel transition when the ionic strength is in-creased, and this is the case when this aqueous solution is introduced into the eye.
The rigidity of the gel can be modified by ajusting the polymer concentration.
The gellan gum product not only has the property of changing form the liquid to the solid phase when placed in a medium of higher ionic strength, but it also prossesses two advantageous additional properties according to the pre-sent invention.
In effect, Gelrite ~ in aqueous solution is thixo-tropic (Figure l) and thermoplastic (Figure 2).
These two properties enable its fluidity to be in-creased by shaking or slightly warming the sample before administration to the eye.
Figure l shows the rheology of a 0.6 % aqueous so-lution of Gelrite ~ at 20 C (shear stress (Pa) versus shear rate ~Sec l)).
Figure 2 shows the shear stress (Pa) versus tempera-ture ( C) behavior [at a constant shear rate of 86 second l]
of a 0.6 % Gelrite ~ solution, after a 30 % dilution :
l) in distilled water ;
The pharmaceutical compositions of the invention are of the type which undergoes liquid-gel phase tran-sition under the effect of an increase in the ionic strength.
They are particularly intended for contacting with physiological liquids. Thus the transition occurs at the contact, as the physiological liquids have a higher tonicity than the one of said compositions.
The compositions of the invention are specially useful for ophtalmic use, but also as injectable form, the formed gel having thus the function of slow-release form, as by intradermic or intramuscular injections, or as galenic form intended for contacting with mucous membranes.
~2~36~ 17277 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 efect, as a result of this drainage, only a small ~raction of the dose administered rémains in contact with the cornea for a ~ew 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 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 eye lotion, the latter, in addition, needing to be administered more ~requently.
Some oftheseimplants function by diffusion. Thus, for example, in the "OCUSERT ~ " system, one weekly appli-cation 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 pro-blems ~or the patients.
Others ~unction by dissolution, and, in this case, since the implants are either soluble or autodegradable ("LACRISERT ~ " system), their duration of action is much shorter.
In all cases, the solid implants possess a major disadvantage in that many patients find it difficult to tolerate the introduction into the conjunctival culs-de-sacs of the solid object represented by this implant.
To solve this problem, galenical forms can be usedwhich are liquid at room temperature and assure a semi-solid form at human body temperature. Such delivery systems ~ 7 17277 are described in US Patent 4,188,373, which propose the use of "PLURONIC ~ polyols".
These "PLURONIC ~ polyols" are thermally gelling polymers in which the polymer concentration ~s chosen in accordance with the desired liquid-gel transltion tempera-ture.
However, with the commercially available "PLUR~NIC
polymers", it is difficult to obtain a gel of suitable rigi-dity while maintaining the transition temperature at physio-logical temperatures, which are of the order: of 25 C -Similarly, Canadian Patent 1,072,413 describes sys-tems containing a therapeutic or other agent (poloxamer), the gelification temperatures of which are made higher than room temperature by using additives.
The thermally gelling systems have many disadvanta-ges, including the risk of gelling before administration by an increase in the ambient te~;perature during packaging or storage, for example.
US Patent 4,474,751 of ~Ierck & Co., relates to other systems for delivering drugs based on thermogelifica-tion of gels, but these systems require very large amounts of polymers and this is not always well tolerated by the eye.
The present invention relates to a pharmaceutical composition intended for contacting with a physiological liquid characterized in that said composition is intended to be administered as a non-gelled liquid form and is inten-ded to gel in situ, this composition containing at least one polysaccharide in aqueous solution, of the type which under-goes liquid-gel phase transition gelling in situ under the effect of an increase in the ionic strength of said physio-logical liquid.
The prefered pharmaceutical composition according ~ 6 ~ 17277 to the invention is an ophthalmological composition, the physiological liquide being the lacrimalfluid. mus, the pre-sent invention overcomes these particular problems of ad-ministering ophthalmic compositions.
As a matter of fact, the composition, 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 introdu-ced into the eye, as a result of the ionic strength of the physiological fluid which is in this case, the lacrimal fluid.
This new ophthalmological composition is an amaz-ingly advantageous form for several reasons. In particular, since the presence of lacrimal fluid is 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 gel-ling during storage.
Also, the polymer used can form a gel at concentra-tions lO- to lO0- fold lower than those used in systems in-volving thermogelification. It is hence very well tolera-ted by the eye.
Finally, when these compositions contain a pharma-ceutically active substance, such a delivery system makes it possible to achieve great bioavailability of the product, and concentrations of active principle which are sustained with time, advantages of a slow delivery system.
Furthermore, in the case of already gelled or semi-solid compositions, it is not possible to administer themby volumetric means, especially when they come from a multi-dose container. To administer these in reproducihle quantities, one is then com elled to employ gravimetric ~8~3~ 7 17277 means.
The compositions according to the invention have, on the one hand, the advantage of liquid ophthalmic compo-sitions, namely reproducible and accurate dosing, by volu-metric means, of the active substance, and on the otherhand the advantages known for the systems in rigid or semi solid gel form, relating to the delivery of active sub-stances.
The composition according to the invention conse-quently has neither the disadvantages of losses of activesubstances 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 Applicant Company has demonstrated that aqueous polysaccharide solutions, of the type which undergoes liquid-gel phase transition under the effect o~ an increase in the ionic strength, and are especially suitable accor-ding to the invention, are solutions of a polysaccharide obtained by fermentation of a microorganism.
Thus, acccrding to the invention, an extracellular anionic heteropolysaccharide elaborated by the bacterium Pseudomonas elodea and known by the name gellan gum is preferably used.
This polysaccharide, manufactured by KELCO & CO., is already used as a gelling agent for culture medium and also in food products. The structure of this heteropolysac-charide consists of the following tetrasaccharide repeating unit :
- 3)-~LD-Glcp-(l~4,-~LD-GlcpA-(l~4)-~-D-Glcp-(l~4)-~-L Rhap-(l~
which may, or may not, be partially C-acetylated on its ~-D-glucopyranose ~-D-Glcp) residues.
-~ 6 ~ 17277 The preparation of such polysaccharides in native and deacetylated form is described, in particular, in Patents US 4,326,053 and 4,326,052 of MERCK & CO., Inc. ~ahway N.~., and their structure has been described, in particular, b~
JANSSON & LINDBERG, Carbohydr. res. 124 (1983) 135-9.
Accordiny to the present invention, aqueous solu~
tions containing about O.l ~ to about 2.0 ~ by weight of gellan gum, and especially of the product known by the tra-dename Gelrite ~ , which is a low acetyl clarified grade of gellan gum, are viscous at low ionic strength but under-go a liquid-gel transition when the ionic strength is in-creased, and this is the case when this aqueous solution is introduced into the eye.
The rigidity of the gel can be modified by ajusting the polymer concentration.
The gellan gum product not only has the property of changing form the liquid to the solid phase when placed in a medium of higher ionic strength, but it also prossesses two advantageous additional properties according to the pre-sent invention.
In effect, Gelrite ~ in aqueous solution is thixo-tropic (Figure l) and thermoplastic (Figure 2).
These two properties enable its fluidity to be in-creased by shaking or slightly warming the sample before administration to the eye.
Figure l shows the rheology of a 0.6 % aqueous so-lution of Gelrite ~ at 20 C (shear stress (Pa) versus shear rate ~Sec l)).
Figure 2 shows the shear stress (Pa) versus tempera-ture ( C) behavior [at a constant shear rate of 86 second l]
of a 0.6 % Gelrite ~ solution, after a 30 % dilution :
l) in distilled water ;
2) in a simulated tear fluid.
_7_ 17277 This latter case of Figure 2 2) shows the increase in viscosity resulting from the dilution of Gelrite in a simulated lacrimal fluid.
Thus, the Applicant Company has demonstrated gel formation in a rabbit's eye following a 20 ~1 instill~tion of a solution containing 0.4 % by weight of Gelrite ~ in deionized water.
The ophthalmic compositions according to the in-vention can be used as they arein variousapplications, and, for example, to maintain adequate hydration of the eye (treatment of dry eye syndrom).
Furthermore, it appears that the ophtalmic compo-sitions accordin~ to the invention are especially suitable for administering to the eye any pharmaceutically acti~e substance administered for curative and/or diagnostic pur~
poses. Thus, the present invention relates to a pharmaceu-tical composition which contains at least one pharmaceuti-cally active substance for curative or diagnostic purposes.
By pharmaceutically active substance, there is un-derstood one or more drugs and/or one or more diagnosticagents. Any active substance can be delivered by the compo-sitions according to the inventioh. The active substance is preferably chosen to be soluble in water, although some active substances show greater solubility than others in the aqueous polysaccharide solutions according to the inven-tion. Furthermore, ~ctive substances can be in suspension or in emulsion (e.g. emulsions of oil droplets, complex li-pidic materials, liposomes) in the agueous polysaccharide solutions. Therefore, the present invention relates to oph-thalmic compositions containing at least one active sub-stance in solution or suspension or emulsion in the aqueous polysaccharide solutionO
The prefered pharmaceu~ically active substance, 36~
used accordin~ to the present invention is timolol or one of its derivatives.
Timolol can be used alone or in combination with other pharmaceutically active agents.
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 0.001 ~ to about 5 % by weight of at least one phar-maceutically active substance.
The quantities relating to the aqueous gellan gum solution make it possible to obtain a suitable gel consis-tency and to compensate the loss lnduced by the steriliza-tion procedures used during the process of manufacture of these ophthalmic compositions.
Other additives can also take part in the ophthal-mic compositions according to the invention. The~e axe, in particular, other polymers suitable for topical applica-tion to the eye, small amounts of acids or bases for ad-justing the pH to values suitable for administration to the eye, nonionic tonicity adjusting agents, surfactants, agents for controlling bacterial contamination or, for example, other additives-for solubilization or stabilization of the active substance, or any other additive which assist in the formulation.
If necessary, the gel-inducing effect of ionized active substances, for example, which are incorporated in the compositions according to the invention, can be neutra-lized by adding to the formulation a suitable ion pair-forming agent.
For example, the slight gelling effect induced by adding 0.1 mg/ml of benzalkonium chloride in a Gelrite solution according to the invention can be eliminated by adding a small amount of acetic acid. The Applicant Company .
~8~6 ~ 17277 has in addition demonstrated that Gelrite ~ solutions according to the invention are compatible with other ~or-mulation ingredients such as various bu~fers and potential ion pair-forming agents.
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 chan~
ging the gelling properties.
Other tonicity adjusting agents can be used, sorbitol or any sugar for example.
For their administration to the eye, the ophthal-mic compositions according to the invention are adminis-tered in liquid ~orm, ~y anv conventional means for deli-vering drops, such as an eye-dropper or, for example, the socalled llocurlETER ~ " system.
The compositions according to the invention can be administered in the usual manner for eye lotions, in the inferior cul-de-sac of the conjunctiva on the outside of the eye.
By way of example, a drop of liquid composition containing about 25 mg of ophthalmic composition enables about 0.0025 mg to about l.25 mg of active substance to be administered.
The active substances, or drugs, or diagnostic agents, used in the pharmaceutical co~positions according -to the invention are preferably suited to the treatment of the disease from which the patient is suffering and/or to the diagnostic method which it is desired to employ.
For example, if the patient is suffering from glaucoma, the active substance chosen in preferably a beta-blocker such as timolol or one of its derivatives.
Toxicological studies prove the good tolerability of gellan gums : acute oral toxicity tests in rats show ~8~36~7 that the lethal dose 50 (LD50) is greater than 5000 mg per kg ; acute toxicity tests by inhalation show that exposure of rats for 4 hours to a nominal concentration of 6.09 mg/l does not cause the death of any animal in a group of 10 animals, ~7hich indicates that the lethal concentration 50 (LC50) is greater than 6.09 mg/l.
DRAIZE-type eye irritation tests in rabbits show that the product is not regarded as an eye irri~ant.
When these compositions contain an active substan-ce, the objective of such a system for delivering theactive substance is to achieve great bioavailability of the substance and concentrations of this substance which are sustained with time.
The drugs or diagnostic agents which can be admin-istered by means of the ophthalmic compositions accordingto the invention are, for example :
antibacterial substances such as beta-lactam antibiotics, such as cefoxitin, n-formamidoylthienamycin and other thienamycin derivatives, tetracyclines, chloramphenicol, neomycin, carbenicillin, colistin, penicillin G, polymyxin B, vancomycin, cefazolin, cephaloridine, chibrorifamycin, gramicidin, bacitracin and sulfonamides ;
aminoglycoside antibiotics such as gentamycin, kanamycin, amikacin, sisomicin and tobramycin ;
nalidixic acid and its analogs such as norfloxacin and the antimicrobial combination fluoroalanine/pentizidone, nitrofurazones and analogs thereof ;
antihistaminics_and decongestants such as pyrilamine, chlorpheniramine, tetrahydrazoline, antazoline and analogs thereof ;
anti-inflammatories such as cortisone, hydrocortisone, hydrocortisone acetate, betamethasone, dexamethasone, dexamethasone sodium phosphate, prednisone, methylpredni-~2~36 ~ 17277 solone, medrysone, fluorometholone, prednisolone, predniso-lone sodium phosphate, triamcinolone, indomethacin, sulindac, its salts and its corresponding sulfides, and analogs thereof ;
miotics and anticholiner~ics such as echothlophate, pllo-carpine, physostigmine salicylate, diisopropyl~luorophos-phate, epinephrine, dipivaloylepinephrine, neostigmine, echothiopate iodide, demecarium bromide, carbamoyl choline chloride, methacholine, bethanechol, and analogs thereof ;
mydriatics such as atropine, homatropine, scopolamine, hydroxyamphetamine, ephedrine, cocaine, tropicamide, phenylephrine, cyclopentolate, oxyphenonium, eucatropine, and analogs thereof ;
other drugs used in the treatment of conditions and lesions lS of the eyes such as :
antiglaucoma drugs for example timolol, and especially its maleic salt and R-timolol and a combination of timolol or R-timolol with pilocarpine, as well as many other adrenergic agonists and/or antigonists ; epinephrine and an epinephrine complex, or prodrugs such as bitartrate, borate, hydrochlori-de and dipivefrine d~rivatives and hyperosmotic agents such as glycerol, mannitol and urea ; carbonic anhydrase inhibitors such as acetazolamide, dichlorphenamide, 2-(p-hydroxyphenyl)-thio-5thiophenesulfonamide, 6-hydroxy-2-benzothiazole-sulfonamide and 6-pivaloyloxy-2-benzothiazolesulfonamide ;
antiparasitic compounds and/or anti-protoæoal compounds such as ivermectin, pyrimethamine, trisulfapidimidine, clindamycin and corticosteroid preparations ;
compounds having antiviral activity such as acyclovir, 5-iodo-2'-deoxyuridine (IDU), adenosine arabinoside (Ara-A), trifluorothymidine, and interferon and interferon-inducing agents such as poly I : C , ~28~ 17277 antifungal agents such as amphotericin B, nystatin, flucy-tosine, natamycin and miconazole ;
anesthetic agents such as etidocaine cocaine, benoxinate, dibucaine hydrochloride, dyclonine hydrochloride, naepaine, phenacaine hydrochloride, piperocaine, proparacaine hydro-_hloride, tetracaine hydrochloride, hexylcaine, buplva-caine, lidocaine, mepivacaine and prilocaine ;
o~hthalmic diagnostic agents, such as :
a) those used to examine the retina such as sodium fluo-rescein ;
b) those used to examine the conjunctiva, cornea and lac-rimal apparatus, such as fluorescein and rose bengai ;
and c) those used to examine abnormal pupillary responses such as methacholine, cocaine, adrenaline, atropine, hydroxyamphetamine and pilocarpine ;
o~hthalmic agents used as adjuncts in surgery, such as alpha-chymotrypsin and hyaluronidase ;
chelating agents such as ethylenediaminetetraacetic acid ~EDTA) and deferoxamine ;
immunosupPressants and anti-metabolites such as methotrex--ate, cyclophosphamide, 6-mercaptopurine and azathioprine ;
and combinations of the compounds mentioned above, such as antibiotics/antiinflammatories combinations such as the combination of neomycin sul~ate and dexamethasone sodium phosphate, and combinations concomitantly treating glaucoma, for example a combination of timolol maleate and aceclidine.
Generally, the tears produced by the eye dilute the active substance and very rapidly deplete the dose of active substance administered by conventional liquid solu-tions.
The compositions containing a polysaccharide in aqueous solution according to the invention, of the type _13_ 17277 which undergoes liquid-gel phase transition under the ef-fect of an increase in the ionic strength, ar~ diluted less rapidly and make it possible to obtain a sustained delivery of the active substance dissolved or suspended in the composition. (To this end, the total ionic strength of the formulation must be kept as low as possible). This prolonged residence time, permitted by the composition according to the present invention, leads to more effec-tive levels of concentration of active su~stance in the lacrimal film.
A test which demonstrates the prolonged presence of the active sukstance after instillation in the eye of a composition according to the invention, and also other characteristics and advantages of the present invention, appear in the Examples and Figures which follow, which illustrate the invention (the percentages being given by weight).
EXAMPLE 1 :
Sim~le o~hthalmic com~osition Solution 1 Solution 2 Solution 3 - Gelrite ~ 0.6 % 0.6 % 0.2 %
- benzalkonium chloride 0.01 ~ 0.005 % --- mannitol 4 % 4 ~ __ 25 - sufficient water to make 100 % 100 % 100 %
~28036 ~ 17277 . -14-EXAMPLE 2 :
Com~osition for deliverinq timolol Solution l Solution 2 Solution 3 - timolol maleate 0.34 % 0.65 % 0.34 - Gelrite ~ 0.6 ~ 0.6 % 0.6 - benzalkonium chloride O.Ol % O.Ol %
- mannitol 4 % 4 % 4 %
- sufficient water to make lO0 % lO0 % lO0 %
EXAMPLE 3 :
.
Comyos_tion_for deliverin~ dexamethasone ~hos~hate Solution l Solution 2 Solution 3 - dexamethasone phosphate O.l % 0.05 % O.l g - Gelrite ~ 0.6 % 0.3 ~ 0.6 - benzalkonium chloride O.Ol % 0.01 % O.Ol %
- mannitol 4 % 4 % 4 %
- sufficient water to make lO0 % ~00 % lO0 %
EXAMPLE 4 :
To demonstrate the prolonged presence of the acti-ve substance in the eye, after instillation of the active substance incorporated in a composition according to the invention, a comparative test was performed.
The removal of fluorescein from the conjunctival sac of rabbits after an instillation of fluorescein solu-tion, either in distilled water or in a vehicle containing 0.6 % Gelrite ~ , was observed by far W radiation.
~ 36~ 17277 In the eyes treated with the aqueous solution, no fluorescein remains 3 hours after the instillation, where-as in the eyes treated with the vehicle containing the Gelrite ~ , fluorescein is still persisting 5 hours a~ter the instillation.
EX~LE 5 :
ComE~o__t_on__or_del_verinq_timolol Studies are carried out in vivo to obtain data concerning the timolol bioavailability from the solution 1 of example 2.
The concentration of timolol in aqueous humor of non-anaes-thetized Albino Rabbits is valued. Single 50 ~1 Instillations of Gelrite ~ Formulations (Example 2 solution 1) and Timoptic ~ commercial solutions, each Containing 0.25 % of timolol are carried out for a comparison purpose. The Gelrite ~ Solutions were Made with 3 Different lots of Gelrite ~ Polymers.
The obtained results are shown in the following table :
_7_ 17277 This latter case of Figure 2 2) shows the increase in viscosity resulting from the dilution of Gelrite in a simulated lacrimal fluid.
Thus, the Applicant Company has demonstrated gel formation in a rabbit's eye following a 20 ~1 instill~tion of a solution containing 0.4 % by weight of Gelrite ~ in deionized water.
The ophthalmic compositions according to the in-vention can be used as they arein variousapplications, and, for example, to maintain adequate hydration of the eye (treatment of dry eye syndrom).
Furthermore, it appears that the ophtalmic compo-sitions accordin~ to the invention are especially suitable for administering to the eye any pharmaceutically acti~e substance administered for curative and/or diagnostic pur~
poses. Thus, the present invention relates to a pharmaceu-tical composition which contains at least one pharmaceuti-cally active substance for curative or diagnostic purposes.
By pharmaceutically active substance, there is un-derstood one or more drugs and/or one or more diagnosticagents. Any active substance can be delivered by the compo-sitions according to the inventioh. The active substance is preferably chosen to be soluble in water, although some active substances show greater solubility than others in the aqueous polysaccharide solutions according to the inven-tion. Furthermore, ~ctive substances can be in suspension or in emulsion (e.g. emulsions of oil droplets, complex li-pidic materials, liposomes) in the agueous polysaccharide solutions. Therefore, the present invention relates to oph-thalmic compositions containing at least one active sub-stance in solution or suspension or emulsion in the aqueous polysaccharide solutionO
The prefered pharmaceu~ically active substance, 36~
used accordin~ to the present invention is timolol or one of its derivatives.
Timolol can be used alone or in combination with other pharmaceutically active agents.
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 0.001 ~ to about 5 % by weight of at least one phar-maceutically active substance.
The quantities relating to the aqueous gellan gum solution make it possible to obtain a suitable gel consis-tency and to compensate the loss lnduced by the steriliza-tion procedures used during the process of manufacture of these ophthalmic compositions.
Other additives can also take part in the ophthal-mic compositions according to the invention. The~e axe, in particular, other polymers suitable for topical applica-tion to the eye, small amounts of acids or bases for ad-justing the pH to values suitable for administration to the eye, nonionic tonicity adjusting agents, surfactants, agents for controlling bacterial contamination or, for example, other additives-for solubilization or stabilization of the active substance, or any other additive which assist in the formulation.
If necessary, the gel-inducing effect of ionized active substances, for example, which are incorporated in the compositions according to the invention, can be neutra-lized by adding to the formulation a suitable ion pair-forming agent.
For example, the slight gelling effect induced by adding 0.1 mg/ml of benzalkonium chloride in a Gelrite solution according to the invention can be eliminated by adding a small amount of acetic acid. The Applicant Company .
~8~6 ~ 17277 has in addition demonstrated that Gelrite ~ solutions according to the invention are compatible with other ~or-mulation ingredients such as various bu~fers and potential ion pair-forming agents.
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 chan~
ging the gelling properties.
Other tonicity adjusting agents can be used, sorbitol or any sugar for example.
For their administration to the eye, the ophthal-mic compositions according to the invention are adminis-tered in liquid ~orm, ~y anv conventional means for deli-vering drops, such as an eye-dropper or, for example, the socalled llocurlETER ~ " system.
The compositions according to the invention can be administered in the usual manner for eye lotions, in the inferior cul-de-sac of the conjunctiva on the outside of the eye.
By way of example, a drop of liquid composition containing about 25 mg of ophthalmic composition enables about 0.0025 mg to about l.25 mg of active substance to be administered.
The active substances, or drugs, or diagnostic agents, used in the pharmaceutical co~positions according -to the invention are preferably suited to the treatment of the disease from which the patient is suffering and/or to the diagnostic method which it is desired to employ.
For example, if the patient is suffering from glaucoma, the active substance chosen in preferably a beta-blocker such as timolol or one of its derivatives.
Toxicological studies prove the good tolerability of gellan gums : acute oral toxicity tests in rats show ~8~36~7 that the lethal dose 50 (LD50) is greater than 5000 mg per kg ; acute toxicity tests by inhalation show that exposure of rats for 4 hours to a nominal concentration of 6.09 mg/l does not cause the death of any animal in a group of 10 animals, ~7hich indicates that the lethal concentration 50 (LC50) is greater than 6.09 mg/l.
DRAIZE-type eye irritation tests in rabbits show that the product is not regarded as an eye irri~ant.
When these compositions contain an active substan-ce, the objective of such a system for delivering theactive substance is to achieve great bioavailability of the substance and concentrations of this substance which are sustained with time.
The drugs or diagnostic agents which can be admin-istered by means of the ophthalmic compositions accordingto the invention are, for example :
antibacterial substances such as beta-lactam antibiotics, such as cefoxitin, n-formamidoylthienamycin and other thienamycin derivatives, tetracyclines, chloramphenicol, neomycin, carbenicillin, colistin, penicillin G, polymyxin B, vancomycin, cefazolin, cephaloridine, chibrorifamycin, gramicidin, bacitracin and sulfonamides ;
aminoglycoside antibiotics such as gentamycin, kanamycin, amikacin, sisomicin and tobramycin ;
nalidixic acid and its analogs such as norfloxacin and the antimicrobial combination fluoroalanine/pentizidone, nitrofurazones and analogs thereof ;
antihistaminics_and decongestants such as pyrilamine, chlorpheniramine, tetrahydrazoline, antazoline and analogs thereof ;
anti-inflammatories such as cortisone, hydrocortisone, hydrocortisone acetate, betamethasone, dexamethasone, dexamethasone sodium phosphate, prednisone, methylpredni-~2~36 ~ 17277 solone, medrysone, fluorometholone, prednisolone, predniso-lone sodium phosphate, triamcinolone, indomethacin, sulindac, its salts and its corresponding sulfides, and analogs thereof ;
miotics and anticholiner~ics such as echothlophate, pllo-carpine, physostigmine salicylate, diisopropyl~luorophos-phate, epinephrine, dipivaloylepinephrine, neostigmine, echothiopate iodide, demecarium bromide, carbamoyl choline chloride, methacholine, bethanechol, and analogs thereof ;
mydriatics such as atropine, homatropine, scopolamine, hydroxyamphetamine, ephedrine, cocaine, tropicamide, phenylephrine, cyclopentolate, oxyphenonium, eucatropine, and analogs thereof ;
other drugs used in the treatment of conditions and lesions lS of the eyes such as :
antiglaucoma drugs for example timolol, and especially its maleic salt and R-timolol and a combination of timolol or R-timolol with pilocarpine, as well as many other adrenergic agonists and/or antigonists ; epinephrine and an epinephrine complex, or prodrugs such as bitartrate, borate, hydrochlori-de and dipivefrine d~rivatives and hyperosmotic agents such as glycerol, mannitol and urea ; carbonic anhydrase inhibitors such as acetazolamide, dichlorphenamide, 2-(p-hydroxyphenyl)-thio-5thiophenesulfonamide, 6-hydroxy-2-benzothiazole-sulfonamide and 6-pivaloyloxy-2-benzothiazolesulfonamide ;
antiparasitic compounds and/or anti-protoæoal compounds such as ivermectin, pyrimethamine, trisulfapidimidine, clindamycin and corticosteroid preparations ;
compounds having antiviral activity such as acyclovir, 5-iodo-2'-deoxyuridine (IDU), adenosine arabinoside (Ara-A), trifluorothymidine, and interferon and interferon-inducing agents such as poly I : C , ~28~ 17277 antifungal agents such as amphotericin B, nystatin, flucy-tosine, natamycin and miconazole ;
anesthetic agents such as etidocaine cocaine, benoxinate, dibucaine hydrochloride, dyclonine hydrochloride, naepaine, phenacaine hydrochloride, piperocaine, proparacaine hydro-_hloride, tetracaine hydrochloride, hexylcaine, buplva-caine, lidocaine, mepivacaine and prilocaine ;
o~hthalmic diagnostic agents, such as :
a) those used to examine the retina such as sodium fluo-rescein ;
b) those used to examine the conjunctiva, cornea and lac-rimal apparatus, such as fluorescein and rose bengai ;
and c) those used to examine abnormal pupillary responses such as methacholine, cocaine, adrenaline, atropine, hydroxyamphetamine and pilocarpine ;
o~hthalmic agents used as adjuncts in surgery, such as alpha-chymotrypsin and hyaluronidase ;
chelating agents such as ethylenediaminetetraacetic acid ~EDTA) and deferoxamine ;
immunosupPressants and anti-metabolites such as methotrex--ate, cyclophosphamide, 6-mercaptopurine and azathioprine ;
and combinations of the compounds mentioned above, such as antibiotics/antiinflammatories combinations such as the combination of neomycin sul~ate and dexamethasone sodium phosphate, and combinations concomitantly treating glaucoma, for example a combination of timolol maleate and aceclidine.
Generally, the tears produced by the eye dilute the active substance and very rapidly deplete the dose of active substance administered by conventional liquid solu-tions.
The compositions containing a polysaccharide in aqueous solution according to the invention, of the type _13_ 17277 which undergoes liquid-gel phase transition under the ef-fect of an increase in the ionic strength, ar~ diluted less rapidly and make it possible to obtain a sustained delivery of the active substance dissolved or suspended in the composition. (To this end, the total ionic strength of the formulation must be kept as low as possible). This prolonged residence time, permitted by the composition according to the present invention, leads to more effec-tive levels of concentration of active su~stance in the lacrimal film.
A test which demonstrates the prolonged presence of the active sukstance after instillation in the eye of a composition according to the invention, and also other characteristics and advantages of the present invention, appear in the Examples and Figures which follow, which illustrate the invention (the percentages being given by weight).
EXAMPLE 1 :
Sim~le o~hthalmic com~osition Solution 1 Solution 2 Solution 3 - Gelrite ~ 0.6 % 0.6 % 0.2 %
- benzalkonium chloride 0.01 ~ 0.005 % --- mannitol 4 % 4 ~ __ 25 - sufficient water to make 100 % 100 % 100 %
~28036 ~ 17277 . -14-EXAMPLE 2 :
Com~osition for deliverinq timolol Solution l Solution 2 Solution 3 - timolol maleate 0.34 % 0.65 % 0.34 - Gelrite ~ 0.6 ~ 0.6 % 0.6 - benzalkonium chloride O.Ol % O.Ol %
- mannitol 4 % 4 % 4 %
- sufficient water to make lO0 % lO0 % lO0 %
EXAMPLE 3 :
.
Comyos_tion_for deliverin~ dexamethasone ~hos~hate Solution l Solution 2 Solution 3 - dexamethasone phosphate O.l % 0.05 % O.l g - Gelrite ~ 0.6 % 0.3 ~ 0.6 - benzalkonium chloride O.Ol % 0.01 % O.Ol %
- mannitol 4 % 4 % 4 %
- sufficient water to make lO0 % ~00 % lO0 %
EXAMPLE 4 :
To demonstrate the prolonged presence of the acti-ve substance in the eye, after instillation of the active substance incorporated in a composition according to the invention, a comparative test was performed.
The removal of fluorescein from the conjunctival sac of rabbits after an instillation of fluorescein solu-tion, either in distilled water or in a vehicle containing 0.6 % Gelrite ~ , was observed by far W radiation.
~ 36~ 17277 In the eyes treated with the aqueous solution, no fluorescein remains 3 hours after the instillation, where-as in the eyes treated with the vehicle containing the Gelrite ~ , fluorescein is still persisting 5 hours a~ter the instillation.
EX~LE 5 :
ComE~o__t_on__or_del_verinq_timolol Studies are carried out in vivo to obtain data concerning the timolol bioavailability from the solution 1 of example 2.
The concentration of timolol in aqueous humor of non-anaes-thetized Albino Rabbits is valued. Single 50 ~1 Instillations of Gelrite ~ Formulations (Example 2 solution 1) and Timoptic ~ commercial solutions, each Containing 0.25 % of timolol are carried out for a comparison purpose. The Gelrite ~ Solutions were Made with 3 Different lots of Gelrite ~ Polymers.
The obtained results are shown in the following table :
3~
O
N ~
H ~ ~ O O
Z ~ O O O O
+1 +1 ~1 +1 H ~ al ' I o o o u~ a.) Q~ -- ^
~ 9 ~ N
+ I
2) ~ N N O O
a~ . . .
~ C~ O O O O
,_1 +1 +1 +1 +1 . , . CO
~ ~ --I O
O oô ~ CO --O
O ~r N --I O
~ O O O O O
+1 + I +l +
U~ ~ ~ O ~
H ~ ~ ~--1 0 l¢
O O O ^ ^
O N N
O ~ +l +l +l +l ~ U~
O H a~ ~9 ~ O
O o ~ ~ ~ _ '~I O O O O O
~ o ~ Z
~r N ~ --I
~ O
O
Z
o o ~\
OO ~ C~ O
z ~ 36~ 17277 The invention is not limited to the above examples ;
the compositions of the invention are also useful for thelr application in all pharmaceutical compositions, which are intended for contacting with -the physiolo~ical liquids.
Thus, the present invention also concerns the injectable compositions, for intradermic or intramuscular injections, and external topical compositions which are intended for contacting with mucous membranes.
O
N ~
H ~ ~ O O
Z ~ O O O O
+1 +1 ~1 +1 H ~ al ' I o o o u~ a.) Q~ -- ^
~ 9 ~ N
+ I
2) ~ N N O O
a~ . . .
~ C~ O O O O
,_1 +1 +1 +1 +1 . , . CO
~ ~ --I O
O oô ~ CO --O
O ~r N --I O
~ O O O O O
+1 + I +l +
U~ ~ ~ O ~
H ~ ~ ~--1 0 l¢
O O O ^ ^
O N N
O ~ +l +l +l +l ~ U~
O H a~ ~9 ~ O
O o ~ ~ ~ _ '~I O O O O O
~ o ~ Z
~r N ~ --I
~ O
O
Z
o o ~\
OO ~ C~ O
z ~ 36~ 17277 The invention is not limited to the above examples ;
the compositions of the invention are also useful for thelr application in all pharmaceutical compositions, which are intended for contacting with -the physiolo~ical liquids.
Thus, the present invention also concerns the injectable compositions, for intradermic or intramuscular injections, and external topical compositions which are intended for contacting with mucous membranes.
Claims (19)
1. Pharmaceutical composition intended for contacting with a physiological liquid characterized in that 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 poly-saccharide 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 physiological liquid.
2. Pharmaceutical composition as claimed in Claim 1, characterized in that said composition is an ophthalmic composition for use in the eye.
3. Composition as claimed in Claim 1 or 2, in which the polysaccharide is obtained by fermentation of a microorganism.
4. Composition as claimed in Claim 3, in which the microorganism is Pseudomonas elodea.
5. Composition as claimed in Claim 1 or 2, in which the polysaccharide has as its basic tetra-saccharide unit ?3) -.beta.-D-Glcp-(1?4)-.beta.-D-GlcpA-(1?4)-.beta.-D-Glcp-(?4)-.alpha.-L-Rhap-(l? which may, or may not, be partially O-acetylated on its .beta.-D-glycopyranosyl resi-dues.
6. Composition as claimed in Claim 1 or 2, which contains 0.1 to 2.0% by weight of the said poly-saccharide.
7. Composition as claimed in Claim 1 or 2, which contains in addition a tonicity adjusting agent.
8. Composition as claimed in Claim 1 or 2, which contains in addition a tonicity adjusting agent which is a sugar such as mannitol or sorbitol.
9. Composition as claimed in Claim 1, which contains at least one phaarmaceutically active sub-stance for curative or diagnostic purposes.
10. Composition as claimed in Claim 2, which contains at least one pharmaceutically active substance for curative or diagnostic purposes.
11. Composition as claimed in Claim 9, in which the pharmaceutically active substance is timolol or a derivative thereof.
12. Composition as claimed in Claim 2, which contains at least one pharmaceutically active substance for curative or diagnostic purposes wherein said phar-maceutically active substance is timolol or a deriva-tive thereof.
13. Composition as claimed in Claim 9, which contains 0.1 to 2.0% by weight of polysaccharide and 0.001 to 5% by weight of at least one pharmaceutically active substance for curative or diagnostic purposes.
14. Composition as claimed in Claim 2, which contains 0.1 to 2.0% by weight of polysaccharide and 0.0001 to 5% by weight of at least one pharmaceutically active substance for curative or diagnostic purposes, wherein said pharmaceutically active substance is timolol or a derivative thereof.
15. Composition as claimed in Claim 1 or 2, in which the pharmaceutically active substance is in solution.
16. Composition as claimed in Claim 1 or 2, in which the pharmaceutically active substance is in suspension.
17. Composition as claimed in claim 1 or 2, in which the pharmaceutically active substance is in emulsion.
18. Injectable composition as claimed in Claim 1 or 2.
19. Composition for application to mucous membrane as claimed in Claim 1 or 2.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8514689A FR2588189B1 (en) | 1985-10-03 | 1985-10-03 | LIQUID-GEL PHASE TRANSITION PHARMACEUTICAL COMPOSITION |
| FR8514689 | 1985-10-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1280367C true CA1280367C (en) | 1991-02-19 |
Family
ID=9323509
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000519753A Expired - Lifetime CA1280367C (en) | 1985-10-03 | 1986-10-03 | Pharmaceutical composition of the type which undergoes liquid-gel phase transition |
Country Status (25)
| Country | Link |
|---|---|
| US (1) | US4861760A (en) |
| EP (1) | EP0227494B1 (en) |
| JP (1) | JPH0667853B2 (en) |
| KR (1) | KR940000229B1 (en) |
| CN (1) | CN1046094C (en) |
| AT (1) | ATE72990T1 (en) |
| AU (1) | AU595240B2 (en) |
| CA (1) | CA1280367C (en) |
| CY (1) | CY1779A (en) |
| DE (2) | DE227494T1 (en) |
| DK (1) | DK170500B1 (en) |
| ES (1) | ES2002401A6 (en) |
| FI (1) | FI91217C (en) |
| FR (1) | FR2588189B1 (en) |
| GR (1) | GR862444B (en) |
| HK (1) | HK42594A (en) |
| IE (1) | IE59464B1 (en) |
| IL (1) | IL80156A (en) |
| LU (1) | LU88694I2 (en) |
| LV (1) | LV5725B4 (en) |
| NL (1) | NL950012I1 (en) |
| NO (2) | NO173212C (en) |
| NZ (1) | NZ217662A (en) |
| PT (1) | PT83471B (en) |
| ZA (1) | ZA867464B (en) |
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-
1986
- 1986-09-17 IE IE248186A patent/IE59464B1/en not_active IP Right Cessation
- 1986-09-23 NZ NZ217662A patent/NZ217662A/en unknown
- 1986-09-25 IL IL80156A patent/IL80156A/en not_active IP Right Cessation
- 1986-09-25 US US06/911,606 patent/US4861760A/en not_active Expired - Lifetime
- 1986-09-25 GR GR862444A patent/GR862444B/en unknown
- 1986-09-26 AU AU63189/86A patent/AU595240B2/en not_active Expired
- 1986-09-30 ZA ZA867464A patent/ZA867464B/en unknown
- 1986-09-30 CN CN86106637A patent/CN1046094C/en not_active Expired - Lifetime
- 1986-10-01 PT PT83471A patent/PT83471B/en unknown
- 1986-10-02 JP JP61233369A patent/JPH0667853B2/en not_active Expired - Lifetime
- 1986-10-02 AT AT86402170T patent/ATE72990T1/en not_active IP Right Cessation
- 1986-10-02 NO NO863916A patent/NO173212C/en unknown
- 1986-10-02 FI FI863990A patent/FI91217C/en not_active IP Right Cessation
- 1986-10-02 DK DK469886A patent/DK170500B1/en not_active IP Right Cessation
- 1986-10-02 EP EP86402170A patent/EP0227494B1/en not_active Expired - Lifetime
- 1986-10-02 LU LU88694C patent/LU88694I2/en unknown
- 1986-10-02 ES ES8602366A patent/ES2002401A6/en not_active Expired
- 1986-10-02 DE DE198686402170T patent/DE227494T1/en active Pending
- 1986-10-02 DE DE8686402170T patent/DE3684121D1/en not_active Expired - Lifetime
- 1986-10-02 KR KR1019860008277A patent/KR940000229B1/en not_active IP Right Cessation
- 1986-10-03 CA CA000519753A patent/CA1280367C/en not_active Expired - Lifetime
-
1994
- 1994-05-05 HK HK42594A patent/HK42594A/en not_active IP Right Cessation
-
1995
- 1995-04-10 NO NO1995003C patent/NO1995003I1/en unknown
- 1995-08-07 NL NL950012C patent/NL950012I1/en unknown
- 1995-08-29 LV LV950262A patent/LV5725B4/en unknown
- 1995-10-20 CY CY177995A patent/CY1779A/en unknown
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