CA1108053A - Sustained release ophthalmic drug dosage - Google Patents
Sustained release ophthalmic drug dosageInfo
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- CA1108053A CA1108053A CA318,447A CA318447A CA1108053A CA 1108053 A CA1108053 A CA 1108053A CA 318447 A CA318447 A CA 318447A CA 1108053 A CA1108053 A CA 1108053A
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- gel
- ophthalmic
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- ophthalmic drug
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Ophthalmology & Optometry (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT
The present invention is directed to an aqueous dispersion of an ophthalmic drug and a high molecular weight polymer which forms a highly viscous gel and can be used to prolong the duration of activity of the ophthalmic drug when the gel is applied into the conjunctival sac of the eye.
The ophthalmic drug-containing gel composition has prolonged retention time in the eye and remains in contact with the surface of the eye for an extended period of time.
The present invention is directed to an aqueous dispersion of an ophthalmic drug and a high molecular weight polymer which forms a highly viscous gel and can be used to prolong the duration of activity of the ophthalmic drug when the gel is applied into the conjunctival sac of the eye.
The ophthalmic drug-containing gel composition has prolonged retention time in the eye and remains in contact with the surface of the eye for an extended period of time.
Description
~ The present invention relates generally to composLtions and a method for treatment of a diseased eye. More particularly, the present invention is directed to the topical administration to the eye of a long-acting, well-retained gel preparation containing an ophthalmic drug.
Yarious ophthalmic drugs have been found to have therapeutic usefulness in treatment of diseases of the eye. Such ophthalmic drugs include pilocarpine, epinephrine, tetracycline, corticosteroids and carbachol. It has been a problem in the use of such ophthalmic drugs to retain the drug in contact with the surface of the eye for a sufficient period to accomplish the therapeutic purpose.
Various methods have beenproposed to increase the time o~ contact of oph~halmic drugs with the eye. For example, United States Patent No. 3j828,777 to Ness describes an ocular device for the controlled and continuous administration of a predetermined dosage of drug to the eye. The ocular device of the Ness patent is a body of micro-porous drug release-rate control-ling material which is insoluble in tear fluid. The por~s of the body are filled with a medium permeable to the passage of a dxug by diffusion. The ~ody further contains a reservoir of a drug formulation confined in the body which is of limited solubility in the medium and which is of a shape that is adapted for insertion and retention in the conjunctival sac. The body continuously meters the flow of a therapeutically effective amount of drug to the eye and surrounding tissues at a controlled rate over a long period of time.
Ocular insert devices are known and are intended for use in prolonging the effect of a drug contained within the ocular ;
insert device. United States Patent No~ 3,811,444 to Teller et al, ~,~1 United States Patent No. 3,826,258 to A~raham et al~ and United States Patent No. 3,786,812 to Neefe are directed to such devices. United States Patent No. 3,845,201 to ~laddad and United States Patent No. 3,914,402 to Shell are directed to prior art solid drug dosage forms. Previously known ointments containing drugs have not been effective in that they are not clear and therefore form a barrier ~o sight or in that they axe rapidly removed by the normal function Qf the eye and the prolonged rate of release of the drug is not attained. United States Patent No. 4,003,991 to Krohn et al is directed to an ophthalmic ointment having a relatively low viscosity which includes a water soluble polymer and a therapeutic agent.
Accordingly, it is a principal object of the pr~sent invention to provide a composition and method for treating a diseased eye.
It is another object of the present invention to provide a composition and method for topical application to an eye which provides a long-acting, well-retained, gel preparation ~0 containing an ophthalmic dxug.
I~ is a further object of the present invention to provide a composition and method for treatment of a diseased e~e wherein an ophthalmic drug is reacted w.ith a polymer to provide a complex and/or salt suitable for topical application to an eye wherein the ophthalmic drug is slowly released from the complex and/or salt.
These and other objects of the invention will become more apparent from the follawing detailed description and the accompanyin~ claims.
.
Generally, the present invention is directed to an aqueous dispersion of an ophthalmic drug and a high molecular weight polymer which forms highly viscous gels and can be used to prolong ~he duration of activity of the ophthalmic drug when the gel is applied into the conjunctival sac of the eye. The prolongation of activity of ~he ophthalmic drug i5 accomplished through slow release of the drug from the gel matrix and/or a slow erosion of gel surface. The dru~ containing gel composi-tions of the present invention have a prolonged retention time in the eye and remain in contact with the surface of the eye for an extended period of time.
The high molecular weight polymers useful in the present invention have a molecular weight of from about 1 million to about 6 million. The polymers are characteri~ed as having c~rboxylic or anhydride functional groups and preferably contàins ~rom 2 to 7 carbon atoms per functional group. The gels which form during the preparation of the ophthalmic drug~polymer dispersion have a viscosity o~ from about ~0,000 ~0 to about ~00,000 cps at 20 rpm (spindle 7) at 25 C generated by an RVT Brookfield Viscometer, preferably from about 75,000 to about 200,000 cps. The viscosity of the gels is too high to be measured with a No. 3 spindle. The gels further are characterized as having a yield value of from about 5,000 to about 20,000 dyne/cm2 ox more as determined by a Ferranti-Shirley Viscometer at 25 C.
The high molecular weight polymers used in the compositions of the present invention not only thicken the compositions to provide a gel, but they also provide a special type of viscosity or rheology i.e., plastic viscosity. Plastic ~8~53 viscosity is indicative o a material that does not flow until a certain force or stress value is exceededl This is referred to as the yield value. While not wishing to be bound by any theory, it is believed that the increased duration of activity of the ophthalmic drug in the gel compositions of the invention is related not only to the apparent viscosi~y (thickness), but is al50 related to thQ yield value. The gel compositions of the pres~nt invention also exhibit the rheological parameter of thixotropy which is related to the break aown and rebuilding of the gel structure. As the gel compositions are sheared above the yield value and begin to flow, the structure is broken down; but when the shear is removed the structure reforms and may even reach the initial high viscosity and yield value.
The high molecular weight polymers useful in the ophthalmic compositions of the present invention are those which are capable of providing the rheolo~ical characteristics of high viscosity and high yield value at the levels set forth herein above.
Suitable polymers useful in the present invention are carboxypolymethylene, a carboxy vinyl polymer, (available under th~ tr~d6-n~ Carbopol from the B. F. Goodrich Company);
and ethylene maleic anhydride, (available under the trade n~ne ~MA from the Monsanto Company). The polymers are used in the gel compositions at a level of from about 2 to about 8 percent by weight.
The compositions and method of the invention are adaptable for use with any of the ophthalmically active drugs, ~8$53 particularly amine drugs known ~or use in the treatment of diseases of the eye. ~hese ophthalmic drugs include pilocarpine, epinephrine, tetracycline, phenylephrine, eserine, phospholine iodide, ~emecarium bromide, c~clopentolate, homatropine, scopolamine, chlortetracycline, bacitracin, neomycin, polymixin, gramicidin, oxyte~racycline, chloramph-enicol, gentamycin, penicillin, erythromycin, carbachol, sulfacetamide, polymixin B, idox~ridine, isoflorophate, fluo~omethalone, dexamethasone, hydrocortisone, hydxo-cortisone acetate, dexamethasone 21-phosphate, fluorocinolone, m~dl~ysone, prednisolone, methyl prednisolone, prednisolone 21-phosphate, prednisolone acetate, betamethasone and triamcinolone.
The ophthalmic drug is present in the gel compositions at a level effective to accomplish the purpose of the drug.
Usual levels of use of the ophthalmic drug are in ~he range o~ from about 0.03 to about 15 percent by weight of the gel composition.
The inven-tion is particularly suitable for prolonging the activi~y of pilocarpine, which has been a goal in oph~halmic treatment o the eye fox a lon~ time. Accordingly, various aspects of the invention are hereinafter particularly described with reference to the use of pilocarpine as the ophthalmic dxug in compositions of the invention.
Several methods have been used to prepare the drug/polymer compositions of the invention. One method, referred to herein as Method A, involves dispersing the polymer in water followed by the addition of a basic ophthalmic drug so as to neutralize the polymerO The neutralization is responsible for the formation of a hydrogel complex of the ophthalmic dru~ and polymer. The final pH is dependent upon the basicity of the ophthalmic drug and the amount added. If the drug is not sufficiently basic, the pH of the hydrogel can be adjusted by adding a basic ma-terial, such as ammonium hydr~xide, sodium hydroxide, ethanolamine or other basic compounds to provide a desired pH. It is pre~erred to provide a pH of from abou-t 4.5 to about 8.5 in the ophthalmic drug/polymer gel formulations. It has also been determined that any ophthalmic drug can be added to a hydrogel formed by addition of a basic (non-drug) agent to the polymer to first form the gel ! followed by addition of the ophthalmic drug in any desixed concentration.
In a second method, referred to herein as Method B, a salt of an ophthalmic drug and the polymer is prepared.
The ophthalmic drug salt is prepared by dispersing the polymer in an inert organic solvent, such as hexane, benzene or chloroform, to ~orm a slurry. Thereafter, a solution of th~ ophthalmic drug in the solvent is added to the slurry.
An acid-base neutraliæation reaction takes place in which the polymer-ophthalmic drug product precipitates from the solvent. After removal o~ the solvent, a finely divided powdered solid remains. For some ophthalmic drugs, such as carbachol, a solid m~ss is produced by the neutralization reaction. The solid mass can be reduced to fine par-ticles by grinding. Thereafter, a gel is prepared by dispersion of the finely divided powdered product in water.
A third method referred to herein as Method C, utilizes the acid salt form of the drug. A non-drug base, such as sodium hydroxide is used to neutralize an aqueous dispersion of the polymer and form a gel followed by addition oi the acid salt ~orm of the drug.
The duration of activity of gel formulations containincJ an ophthalmic drug prepared by all ~hree methods described herein is at least twice the duration of commercial ophthalmic drug preparations. A study of pilocarpine formulations complexed with carboxypolymethylene by the Method A procedure indicates that these gel formulations are unique in that ~hey remain in the conjunctival sac of a rabbit for a period of ~ to 8 hours. Prior art formulations, such as petrolatum salves or suspensions of slightly soluble salts of pilocarpine have been found to be ~lushed from the rabbit eye in a period of lS to 30 minutes.
In a further embodiment of the present invention inely divided particles of an ophthalmic drug salt of the lS polymer prepared in accordance with Method B is suspended in a non-aqueous vehicla, such as stabilized oil, e.g.
mineral oil, vegetable oil and silicone fluid. Thereafter, the suspended particles are administered directly into the ~ye. A gel i~mediately forms with the eye by reaction of the particles with the tears of the eye. Pilocarpine salts of car~oxypolymethylene containing 2 mg of pilocarpine per c~ose have yielded miosis durations of 14 hours in rabbit eyes, whereas, aqueous solutions oE pilocarpine have miosis durations of only 4 to 6 hours.
In a still further embodiment the ophthalmic drug salt particles can be placed directly in the eye by any suita~le means. The particles then gel in si-tu in the eye by reaction with the teaxs of the eye.
The following examples further illustxate varioua feature~ of the invention ! but are intended to no way limit the scope of the invention whlch is set ~orth in the appencled claims~
i;3 EXAMPLE I
A salt form of carboxypolymethylene and pilocarpine is prepared by Method B, six grams of carboxypolymethylene (available usa4~-~he~ e-~a~e-CarbopolQ940 from B. Fo Goodrich Co.) is stirred into 30 ml o~ hexane. Four grams of pilocarpine is ~issolved in 30 ml of hexane~ The pilocarpine solution is then blended with the suspension o~ carboxypolymethylene. ~n acid-base neutralization ~eacti~n occurs to orm a salt of pilocarpine and carboxy-methylene. The salt form of carboxymethylene and pilocarpine is recovered from the hexane carrier in the orm of a finely divided powder containing about 35 to 40 percent by weight of pilocarpine.
Two gel formulations are prepared containing the pilocarpine/carboxypolymethylene salt. The gel formulations contain the ingredients indicated hereinbelow in Table I at the indicated level.
TABLE I
~ by weight In~redient Formulation A Formulation B
Carbo~ypolymethylene/
Pilocarpine Salt 5.15 5.15 Benzalkonium Chloride (U.S.P.) 0.01 0.01 Sodium Hydroxide (3N) qs~pH 5.35 qs-pH 6.0 Purified Water qs 100 qs 100 The procedure for obtaining 100 gram of finished gel consists o~ adding Benzalkonlum Chloride to 80 gram of purified water. The benzalkonium chloride solution is stirred as the salt form powder of carboxypolymethylene/
'pilocarpine is quickly added~ The solution is vigorously stirred so as to wet as much of the salt ~oxm powder as possible before the gel forms in about one to two minutes.
Stirring is continued until there is no fur~her apparent hydration. Sufficient sodium hydroxide is then added incrementally to provide the indicated pH. Puriied water is then stirred into the gel to bring the final gel weight to 100 gram. The gel prepara~ion is auto~laved at 120 C
or 20 minutes followed by fast exhaust. The finished gel may contain air bubbles which can be removed by centrifugation.
Using the Ferranti-Shirley Viscometer under the following conditions: 3X Switch Position, 60 seconds sweep, medium cone and 100 rpm spring constantl the following viscosity determinations are obtalned:
....
TA~LE II
A A B B _ 25 C37 C 25 C 37~ C
.
Plastic 740708 546 804 Viscosity (CPS) Yield 1142110778 13351 11421 ~alue 2 (DYNE/CM ) Human miosis data is obtained by placing 50 microliter - doses of formulation A and B into the let eye o nine healthy hllman volunteers. The untreated right eye serves as the control. Formulations A and B and the control formulation of a standard pilocarpine solu~ion contain the equivalent of 2 percent pilocarpine by weight. The following data is obtained.
TABLE IlI
Treated pupil diameter minus control pupil diameter.
Time (hr) ~ B Control 2%
Pilocarpine Solution Pupil ~iameter Dif~erences (mm) 1 2.42 2.33 2.50 3 2.~ 2.56 '1.~3 6 2.56 2.44 1.19 9 1.81 1.89 0.72 12 1.39 1.17 0.64 24 0.17 0.06 -0.19 The larger pupil diameter differenoes following 1 hour for gel compositions A and B compared to the control illustrate the longer duration of the gel compositions of the invention.
Example II
Yarious ophthalmic drugs have been found to have therapeutic usefulness in treatment of diseases of the eye. Such ophthalmic drugs include pilocarpine, epinephrine, tetracycline, corticosteroids and carbachol. It has been a problem in the use of such ophthalmic drugs to retain the drug in contact with the surface of the eye for a sufficient period to accomplish the therapeutic purpose.
Various methods have beenproposed to increase the time o~ contact of oph~halmic drugs with the eye. For example, United States Patent No. 3j828,777 to Ness describes an ocular device for the controlled and continuous administration of a predetermined dosage of drug to the eye. The ocular device of the Ness patent is a body of micro-porous drug release-rate control-ling material which is insoluble in tear fluid. The por~s of the body are filled with a medium permeable to the passage of a dxug by diffusion. The ~ody further contains a reservoir of a drug formulation confined in the body which is of limited solubility in the medium and which is of a shape that is adapted for insertion and retention in the conjunctival sac. The body continuously meters the flow of a therapeutically effective amount of drug to the eye and surrounding tissues at a controlled rate over a long period of time.
Ocular insert devices are known and are intended for use in prolonging the effect of a drug contained within the ocular ;
insert device. United States Patent No~ 3,811,444 to Teller et al, ~,~1 United States Patent No. 3,826,258 to A~raham et al~ and United States Patent No. 3,786,812 to Neefe are directed to such devices. United States Patent No. 3,845,201 to ~laddad and United States Patent No. 3,914,402 to Shell are directed to prior art solid drug dosage forms. Previously known ointments containing drugs have not been effective in that they are not clear and therefore form a barrier ~o sight or in that they axe rapidly removed by the normal function Qf the eye and the prolonged rate of release of the drug is not attained. United States Patent No. 4,003,991 to Krohn et al is directed to an ophthalmic ointment having a relatively low viscosity which includes a water soluble polymer and a therapeutic agent.
Accordingly, it is a principal object of the pr~sent invention to provide a composition and method for treating a diseased eye.
It is another object of the present invention to provide a composition and method for topical application to an eye which provides a long-acting, well-retained, gel preparation ~0 containing an ophthalmic dxug.
I~ is a further object of the present invention to provide a composition and method for treatment of a diseased e~e wherein an ophthalmic drug is reacted w.ith a polymer to provide a complex and/or salt suitable for topical application to an eye wherein the ophthalmic drug is slowly released from the complex and/or salt.
These and other objects of the invention will become more apparent from the follawing detailed description and the accompanyin~ claims.
.
Generally, the present invention is directed to an aqueous dispersion of an ophthalmic drug and a high molecular weight polymer which forms highly viscous gels and can be used to prolong ~he duration of activity of the ophthalmic drug when the gel is applied into the conjunctival sac of the eye. The prolongation of activity of ~he ophthalmic drug i5 accomplished through slow release of the drug from the gel matrix and/or a slow erosion of gel surface. The dru~ containing gel composi-tions of the present invention have a prolonged retention time in the eye and remain in contact with the surface of the eye for an extended period of time.
The high molecular weight polymers useful in the present invention have a molecular weight of from about 1 million to about 6 million. The polymers are characteri~ed as having c~rboxylic or anhydride functional groups and preferably contàins ~rom 2 to 7 carbon atoms per functional group. The gels which form during the preparation of the ophthalmic drug~polymer dispersion have a viscosity o~ from about ~0,000 ~0 to about ~00,000 cps at 20 rpm (spindle 7) at 25 C generated by an RVT Brookfield Viscometer, preferably from about 75,000 to about 200,000 cps. The viscosity of the gels is too high to be measured with a No. 3 spindle. The gels further are characterized as having a yield value of from about 5,000 to about 20,000 dyne/cm2 ox more as determined by a Ferranti-Shirley Viscometer at 25 C.
The high molecular weight polymers used in the compositions of the present invention not only thicken the compositions to provide a gel, but they also provide a special type of viscosity or rheology i.e., plastic viscosity. Plastic ~8~53 viscosity is indicative o a material that does not flow until a certain force or stress value is exceededl This is referred to as the yield value. While not wishing to be bound by any theory, it is believed that the increased duration of activity of the ophthalmic drug in the gel compositions of the invention is related not only to the apparent viscosi~y (thickness), but is al50 related to thQ yield value. The gel compositions of the pres~nt invention also exhibit the rheological parameter of thixotropy which is related to the break aown and rebuilding of the gel structure. As the gel compositions are sheared above the yield value and begin to flow, the structure is broken down; but when the shear is removed the structure reforms and may even reach the initial high viscosity and yield value.
The high molecular weight polymers useful in the ophthalmic compositions of the present invention are those which are capable of providing the rheolo~ical characteristics of high viscosity and high yield value at the levels set forth herein above.
Suitable polymers useful in the present invention are carboxypolymethylene, a carboxy vinyl polymer, (available under th~ tr~d6-n~ Carbopol from the B. F. Goodrich Company);
and ethylene maleic anhydride, (available under the trade n~ne ~MA from the Monsanto Company). The polymers are used in the gel compositions at a level of from about 2 to about 8 percent by weight.
The compositions and method of the invention are adaptable for use with any of the ophthalmically active drugs, ~8$53 particularly amine drugs known ~or use in the treatment of diseases of the eye. ~hese ophthalmic drugs include pilocarpine, epinephrine, tetracycline, phenylephrine, eserine, phospholine iodide, ~emecarium bromide, c~clopentolate, homatropine, scopolamine, chlortetracycline, bacitracin, neomycin, polymixin, gramicidin, oxyte~racycline, chloramph-enicol, gentamycin, penicillin, erythromycin, carbachol, sulfacetamide, polymixin B, idox~ridine, isoflorophate, fluo~omethalone, dexamethasone, hydrocortisone, hydxo-cortisone acetate, dexamethasone 21-phosphate, fluorocinolone, m~dl~ysone, prednisolone, methyl prednisolone, prednisolone 21-phosphate, prednisolone acetate, betamethasone and triamcinolone.
The ophthalmic drug is present in the gel compositions at a level effective to accomplish the purpose of the drug.
Usual levels of use of the ophthalmic drug are in ~he range o~ from about 0.03 to about 15 percent by weight of the gel composition.
The inven-tion is particularly suitable for prolonging the activi~y of pilocarpine, which has been a goal in oph~halmic treatment o the eye fox a lon~ time. Accordingly, various aspects of the invention are hereinafter particularly described with reference to the use of pilocarpine as the ophthalmic dxug in compositions of the invention.
Several methods have been used to prepare the drug/polymer compositions of the invention. One method, referred to herein as Method A, involves dispersing the polymer in water followed by the addition of a basic ophthalmic drug so as to neutralize the polymerO The neutralization is responsible for the formation of a hydrogel complex of the ophthalmic dru~ and polymer. The final pH is dependent upon the basicity of the ophthalmic drug and the amount added. If the drug is not sufficiently basic, the pH of the hydrogel can be adjusted by adding a basic ma-terial, such as ammonium hydr~xide, sodium hydroxide, ethanolamine or other basic compounds to provide a desired pH. It is pre~erred to provide a pH of from abou-t 4.5 to about 8.5 in the ophthalmic drug/polymer gel formulations. It has also been determined that any ophthalmic drug can be added to a hydrogel formed by addition of a basic (non-drug) agent to the polymer to first form the gel ! followed by addition of the ophthalmic drug in any desixed concentration.
In a second method, referred to herein as Method B, a salt of an ophthalmic drug and the polymer is prepared.
The ophthalmic drug salt is prepared by dispersing the polymer in an inert organic solvent, such as hexane, benzene or chloroform, to ~orm a slurry. Thereafter, a solution of th~ ophthalmic drug in the solvent is added to the slurry.
An acid-base neutraliæation reaction takes place in which the polymer-ophthalmic drug product precipitates from the solvent. After removal o~ the solvent, a finely divided powdered solid remains. For some ophthalmic drugs, such as carbachol, a solid m~ss is produced by the neutralization reaction. The solid mass can be reduced to fine par-ticles by grinding. Thereafter, a gel is prepared by dispersion of the finely divided powdered product in water.
A third method referred to herein as Method C, utilizes the acid salt form of the drug. A non-drug base, such as sodium hydroxide is used to neutralize an aqueous dispersion of the polymer and form a gel followed by addition oi the acid salt ~orm of the drug.
The duration of activity of gel formulations containincJ an ophthalmic drug prepared by all ~hree methods described herein is at least twice the duration of commercial ophthalmic drug preparations. A study of pilocarpine formulations complexed with carboxypolymethylene by the Method A procedure indicates that these gel formulations are unique in that ~hey remain in the conjunctival sac of a rabbit for a period of ~ to 8 hours. Prior art formulations, such as petrolatum salves or suspensions of slightly soluble salts of pilocarpine have been found to be ~lushed from the rabbit eye in a period of lS to 30 minutes.
In a further embodiment of the present invention inely divided particles of an ophthalmic drug salt of the lS polymer prepared in accordance with Method B is suspended in a non-aqueous vehicla, such as stabilized oil, e.g.
mineral oil, vegetable oil and silicone fluid. Thereafter, the suspended particles are administered directly into the ~ye. A gel i~mediately forms with the eye by reaction of the particles with the tears of the eye. Pilocarpine salts of car~oxypolymethylene containing 2 mg of pilocarpine per c~ose have yielded miosis durations of 14 hours in rabbit eyes, whereas, aqueous solutions oE pilocarpine have miosis durations of only 4 to 6 hours.
In a still further embodiment the ophthalmic drug salt particles can be placed directly in the eye by any suita~le means. The particles then gel in si-tu in the eye by reaction with the teaxs of the eye.
The following examples further illustxate varioua feature~ of the invention ! but are intended to no way limit the scope of the invention whlch is set ~orth in the appencled claims~
i;3 EXAMPLE I
A salt form of carboxypolymethylene and pilocarpine is prepared by Method B, six grams of carboxypolymethylene (available usa4~-~he~ e-~a~e-CarbopolQ940 from B. Fo Goodrich Co.) is stirred into 30 ml o~ hexane. Four grams of pilocarpine is ~issolved in 30 ml of hexane~ The pilocarpine solution is then blended with the suspension o~ carboxypolymethylene. ~n acid-base neutralization ~eacti~n occurs to orm a salt of pilocarpine and carboxy-methylene. The salt form of carboxymethylene and pilocarpine is recovered from the hexane carrier in the orm of a finely divided powder containing about 35 to 40 percent by weight of pilocarpine.
Two gel formulations are prepared containing the pilocarpine/carboxypolymethylene salt. The gel formulations contain the ingredients indicated hereinbelow in Table I at the indicated level.
TABLE I
~ by weight In~redient Formulation A Formulation B
Carbo~ypolymethylene/
Pilocarpine Salt 5.15 5.15 Benzalkonium Chloride (U.S.P.) 0.01 0.01 Sodium Hydroxide (3N) qs~pH 5.35 qs-pH 6.0 Purified Water qs 100 qs 100 The procedure for obtaining 100 gram of finished gel consists o~ adding Benzalkonlum Chloride to 80 gram of purified water. The benzalkonium chloride solution is stirred as the salt form powder of carboxypolymethylene/
'pilocarpine is quickly added~ The solution is vigorously stirred so as to wet as much of the salt ~oxm powder as possible before the gel forms in about one to two minutes.
Stirring is continued until there is no fur~her apparent hydration. Sufficient sodium hydroxide is then added incrementally to provide the indicated pH. Puriied water is then stirred into the gel to bring the final gel weight to 100 gram. The gel prepara~ion is auto~laved at 120 C
or 20 minutes followed by fast exhaust. The finished gel may contain air bubbles which can be removed by centrifugation.
Using the Ferranti-Shirley Viscometer under the following conditions: 3X Switch Position, 60 seconds sweep, medium cone and 100 rpm spring constantl the following viscosity determinations are obtalned:
....
TA~LE II
A A B B _ 25 C37 C 25 C 37~ C
.
Plastic 740708 546 804 Viscosity (CPS) Yield 1142110778 13351 11421 ~alue 2 (DYNE/CM ) Human miosis data is obtained by placing 50 microliter - doses of formulation A and B into the let eye o nine healthy hllman volunteers. The untreated right eye serves as the control. Formulations A and B and the control formulation of a standard pilocarpine solu~ion contain the equivalent of 2 percent pilocarpine by weight. The following data is obtained.
TABLE IlI
Treated pupil diameter minus control pupil diameter.
Time (hr) ~ B Control 2%
Pilocarpine Solution Pupil ~iameter Dif~erences (mm) 1 2.42 2.33 2.50 3 2.~ 2.56 '1.~3 6 2.56 2.44 1.19 9 1.81 1.89 0.72 12 1.39 1.17 0.64 24 0.17 0.06 -0.19 The larger pupil diameter differenoes following 1 hour for gel compositions A and B compared to the control illustrate the longer duration of the gel compositions of the invention.
Example II
2~ Three additional formulations are prepared and used to determine rabbit miosis data. The formulations contain the indicated ingredients at the levels indicated helow:
~8~53 TAB~E IV
Formulations ~ B C
Ingredients Pilocarpine HCl, U.S.P. 2.0 grams - -Pilocarpine - 1.7 grams Carboxypolymethylene/
Pilocarpine Salt - - 5.15 grams Carboxypolymethylene (~arbopol 940 from B. F. Goodrich Co.) 3.38 grams 3.38 grams Benzalkonium Chloride -.
(U.S.P.) O.01-grams 0.01 grams 0.01 grams Sodium Hydroxide, 3N ~s pH 5.4 qs pH 5.4 qs pH 5.4 .. , '' ' ;
lS Purified Water qs lO0 gxams qs 100 grams qs 100 grams Formulation C of Table IV is prepared as set forth hereinabove under Exa~ple I and is identical to Formulation A of Ex~mple I.
Formulation A of Table IV is prepared as ollows:
Pilocar~ine HCl and Benzalkonium Chloride are dissolved in 80 grams of purified water. While vigorously stirring this solution, carboxypolymethylene is slowly added to the vortex.
Agitation is continued until a cloudy solution without lumps is attainea.
~12-8~:~i3 After stirring is stopped, the entrapped air is allowed to escape. A 10 gram solution containing about 95 percent of the molar requirement of sodium hydroxide is slowly added to the cloudy solution with stirring. A gel rapidly forms as stirring is continued for 10 to 20 minutes. The gel is stored overnight under refrigeration to complete the hydration and allow the pH to come to equilibrium. The final pH of the finished gel is adjusted by adding 3N
Sodium Hydroxide dropwise, and mixîng well with each incremental addition. Purified water is then stirred into the gel to bring the gel weight up to the final weiyht of 100 gram. If the ~inished gel contains air bubbles, they are removed by centrifugatiorl.
Formulation B of Table IV is prepared as follows:
Benzalkonium Chloride is dissolved in 80 gram of purified water. While vigorously stirring this solution, carboxypoly-methylene is siowly added to the vortex. Agitation is co~tinued until a cloudy suspension without lumps is attained.
~fter stirring is stopped, entrapped air is allowed to escape. A 10 gram solution containing pilocarpine is prepared arld is slowly added to the carboxypolymethylene solution with stirring. A gel rapidly forms. Stirring is continued for 10 to 20 minutes. The pH of the gel is brought to within 0.1 to 0.2 pH of the desired pH by the addition of 3N Sodium Hydroxide, mixing well after each incremen-tal addition of sodium hydroxide. The gel is stored overnight under refrigeration to allow the pH to come to equilibrium.
The final pH is adjusted to 5.~ and purified water is added ~ the gel to bring its weight up to the final weight o 100 ~rants. If the finished gel contains air bubbles they are xemoved by centrifu~ation.
The final pH of Formulation A and Formulation B is measured and found to be 5.35. A rheograph is generated ~sing a Ferranti-Shirle~ Viscometer under tlle ~ollowing condition: 2X Switch position, 60 seconds sweep, medium conè and 100 rpm spring constant~ The viscosity de~erminations obtained are:
TABLE V
- Formulation ;~
A (37~ C) B (37 C) Plastic Viscosity 784 910 r (CPS ) -Yield Value 11480 14~60 (DYNE/CM2) Miosis-Time Data usin~ 6 albino rabbîts is obtained for the various ~ormulations o Table IV and a control ormulation of a pilocarpine solution as described hereinabove in Example I. The miosis data is set forth hereinbelow in Table VI.
Control 2~
Pupil Diameter (mm) - - _ Pilocarpine Time ~Hr) A B C Solution 0 5.29 5.35 5.18 5 0.5 3.46 3.43 3.62 3.21 l.0 3.44 3.40 3.46 3.42 2.S 3.22 3.46 3.60 4.20
~8~53 TAB~E IV
Formulations ~ B C
Ingredients Pilocarpine HCl, U.S.P. 2.0 grams - -Pilocarpine - 1.7 grams Carboxypolymethylene/
Pilocarpine Salt - - 5.15 grams Carboxypolymethylene (~arbopol 940 from B. F. Goodrich Co.) 3.38 grams 3.38 grams Benzalkonium Chloride -.
(U.S.P.) O.01-grams 0.01 grams 0.01 grams Sodium Hydroxide, 3N ~s pH 5.4 qs pH 5.4 qs pH 5.4 .. , '' ' ;
lS Purified Water qs lO0 gxams qs 100 grams qs 100 grams Formulation C of Table IV is prepared as set forth hereinabove under Exa~ple I and is identical to Formulation A of Ex~mple I.
Formulation A of Table IV is prepared as ollows:
Pilocar~ine HCl and Benzalkonium Chloride are dissolved in 80 grams of purified water. While vigorously stirring this solution, carboxypolymethylene is slowly added to the vortex.
Agitation is continued until a cloudy solution without lumps is attainea.
~12-8~:~i3 After stirring is stopped, the entrapped air is allowed to escape. A 10 gram solution containing about 95 percent of the molar requirement of sodium hydroxide is slowly added to the cloudy solution with stirring. A gel rapidly forms as stirring is continued for 10 to 20 minutes. The gel is stored overnight under refrigeration to complete the hydration and allow the pH to come to equilibrium. The final pH of the finished gel is adjusted by adding 3N
Sodium Hydroxide dropwise, and mixîng well with each incremental addition. Purified water is then stirred into the gel to bring the gel weight up to the final weiyht of 100 gram. If the ~inished gel contains air bubbles, they are removed by centrifugatiorl.
Formulation B of Table IV is prepared as follows:
Benzalkonium Chloride is dissolved in 80 gram of purified water. While vigorously stirring this solution, carboxypoly-methylene is siowly added to the vortex. Agitation is co~tinued until a cloudy suspension without lumps is attained.
~fter stirring is stopped, entrapped air is allowed to escape. A 10 gram solution containing pilocarpine is prepared arld is slowly added to the carboxypolymethylene solution with stirring. A gel rapidly forms. Stirring is continued for 10 to 20 minutes. The pH of the gel is brought to within 0.1 to 0.2 pH of the desired pH by the addition of 3N Sodium Hydroxide, mixing well after each incremen-tal addition of sodium hydroxide. The gel is stored overnight under refrigeration to allow the pH to come to equilibrium.
The final pH is adjusted to 5.~ and purified water is added ~ the gel to bring its weight up to the final weight o 100 ~rants. If the finished gel contains air bubbles they are xemoved by centrifu~ation.
The final pH of Formulation A and Formulation B is measured and found to be 5.35. A rheograph is generated ~sing a Ferranti-Shirle~ Viscometer under tlle ~ollowing condition: 2X Switch position, 60 seconds sweep, medium conè and 100 rpm spring constant~ The viscosity de~erminations obtained are:
TABLE V
- Formulation ;~
A (37~ C) B (37 C) Plastic Viscosity 784 910 r (CPS ) -Yield Value 11480 14~60 (DYNE/CM2) Miosis-Time Data usin~ 6 albino rabbîts is obtained for the various ~ormulations o Table IV and a control ormulation of a pilocarpine solution as described hereinabove in Example I. The miosis data is set forth hereinbelow in Table VI.
Control 2~
Pupil Diameter (mm) - - _ Pilocarpine Time ~Hr) A B C Solution 0 5.29 5.35 5.18 5 0.5 3.46 3.43 3.62 3.21 l.0 3.44 3.40 3.46 3.42 2.S 3.22 3.46 3.60 4.20
3.S 3~61 3.56 3.77 4.66
4.5 3.85 3.7~ 4.0~ 5.32 l05.5 ~.35 ~.33 4.08, 7.5 ~.79 5.0~ 4.69 -8.5 5,02 4.57 4.54 9.5 5.15 ~.90 ~.70 -l0.5 - 5.0 4.65 15ll.5 - 5.l 5,25 ~. . .
The topically applied ophthalmic gel compositions of the inventioII provide a therapeutic composition with prolonged retention and slow drug rel~ase which can be used for various dlseased conditions of the eye, particularl~ glaucoma when the active agent is pilocarpine, epinephrine or carbachol. The known prior art ophthalmic compositions with slow re]easing properties are either solid inserts, flakes of various compositions and desiyn, or suspensions which are steroid preparation6 or ointment dosage forms. The ointment dosage -Eorms primaril~ contain petrolatum and small quantities of lanolin or its derivatives. A further known ointment dosage form consists of polyethylene containing liguid petrolatum trapped within its matrix. The prior art ointment dosage forms are substantially oleaginous and are not cosmetically appealing since they are greasy and blur the vision. In addition they have been ~ound to prolong therapeutic or pharmalogical activity by approximately 25 percent at best compared to aqueous preparations, whereas the ophthalmic drug/polymer gel compositions in the present invention have prolonged activity two to three times when compared to aqueous solutions. Moreover, the gel compositions o the present invention contain about 95 percent by weight of water trapped within the polymer matrix and are not greasy, are clear so that the vision is not blurred and their refractive index is similar to that of tears.
Example III
In acGordance with method C, the acid salt form of pilocarpine is incorporated within a gel made from ethylene maleic anhydride (available under the trade name of E~A-91 from Monsanto)~ Two gel preparations are prepared and contain the ingredi.ents indicated h~rein below in Table VII.
?.0 Table VII
% by weight Ingredient Formulation A Formulation B
Ethylene maleic anhydride 3.38 5.0 Pilocarpine hydrochloride (U.S.P.) 1.90 2.0 28~ am~lonium hydroxide 2.27 3.5 Mannitol, N.F. 1.9 2.0 Benalkonium chloride (U.S.P.) 0.01 0.01 Purified water qs qs The procedure for preparing 100 grams of finished gel consists of adding ethylene maleic anhydride to the vortex of 25 ml of vigorously stirred water using a high speed mixer. One minute of mi~ing was sufficient in order to completely wet and di.sperse the polymer. ~mmonium hydroxide was added to the dispersion and mixed for one or two minutes until a riyid gel was formed. Pilo-i8~;3 .
carpine hydrochloride, mannitol and benzalkonium chloride were dissolved in 15 ml of purified water and added to ~he gel. This mixture is stirred for 4 minutes. A pH reading of
The topically applied ophthalmic gel compositions of the inventioII provide a therapeutic composition with prolonged retention and slow drug rel~ase which can be used for various dlseased conditions of the eye, particularl~ glaucoma when the active agent is pilocarpine, epinephrine or carbachol. The known prior art ophthalmic compositions with slow re]easing properties are either solid inserts, flakes of various compositions and desiyn, or suspensions which are steroid preparation6 or ointment dosage forms. The ointment dosage -Eorms primaril~ contain petrolatum and small quantities of lanolin or its derivatives. A further known ointment dosage form consists of polyethylene containing liguid petrolatum trapped within its matrix. The prior art ointment dosage forms are substantially oleaginous and are not cosmetically appealing since they are greasy and blur the vision. In addition they have been ~ound to prolong therapeutic or pharmalogical activity by approximately 25 percent at best compared to aqueous preparations, whereas the ophthalmic drug/polymer gel compositions in the present invention have prolonged activity two to three times when compared to aqueous solutions. Moreover, the gel compositions o the present invention contain about 95 percent by weight of water trapped within the polymer matrix and are not greasy, are clear so that the vision is not blurred and their refractive index is similar to that of tears.
Example III
In acGordance with method C, the acid salt form of pilocarpine is incorporated within a gel made from ethylene maleic anhydride (available under the trade name of E~A-91 from Monsanto)~ Two gel preparations are prepared and contain the ingredi.ents indicated h~rein below in Table VII.
?.0 Table VII
% by weight Ingredient Formulation A Formulation B
Ethylene maleic anhydride 3.38 5.0 Pilocarpine hydrochloride (U.S.P.) 1.90 2.0 28~ am~lonium hydroxide 2.27 3.5 Mannitol, N.F. 1.9 2.0 Benalkonium chloride (U.S.P.) 0.01 0.01 Purified water qs qs The procedure for preparing 100 grams of finished gel consists of adding ethylene maleic anhydride to the vortex of 25 ml of vigorously stirred water using a high speed mixer. One minute of mi~ing was sufficient in order to completely wet and di.sperse the polymer. ~mmonium hydroxide was added to the dispersion and mixed for one or two minutes until a riyid gel was formed. Pilo-i8~;3 .
carpine hydrochloride, mannitol and benzalkonium chloride were dissolved in 15 ml of purified water and added to ~he gel. This mixture is stirred for 4 minutes. A pH reading of
5.1 is obtained.
Using a Brookfield RVT Viscometer at 20 rpm equipped with spindle ~7, and also using a Ferranti-Shirley Viscometer under the following conditions; 3X switch position, 60 second sweep;
medium cone and 100 rpm spring constan-t, the ~ollowing viscosity determinations are obtained:
Table VIII
` ~4C 25C 37C
Brookfield Viscosity (cps) 123,000 - -F~rranti-Shirley Plastic Viscosity ~cps) ~ 434 384 Ferranti-Shirley Yield Value (dynes/cm2) - 7,61~ 7,077 2~C 25C 37C
Brookfield Viscosity (cps) 109,000 ~ ~
Ferranti-Shirley Plastic Viscosity ~cps) - 692 558 Ferranti-Shirley Yield Value (dynes/cm2) - 10,081 11,046 Miosis-time data using 6 albino rabbits is obtained from formu-lations A and B of Table VII and a control formulation of a pilocarpine hydrochloride aqueous solution. The miosis data is set forth herein below in Table IX. Fifty microliter doses were ~iven.
Tabie IX
Control 2~
Pupil Diameter (mm) Pilocarpine Time (Hr) A B Solution 0 4.92 5.06 5.08 ~.5 3,72 3.53 3.~3 1.~ 3.23 3.27 3.55 2.0 3.37 3.32 4.05 3.0 3.57 3.13 ~.63 3.5 3.55 3.38 ~.73 4.5 3.67 3.5$ ~.g8 5.5 3.77 3,77 5.20
Using a Brookfield RVT Viscometer at 20 rpm equipped with spindle ~7, and also using a Ferranti-Shirley Viscometer under the following conditions; 3X switch position, 60 second sweep;
medium cone and 100 rpm spring constan-t, the ~ollowing viscosity determinations are obtained:
Table VIII
` ~4C 25C 37C
Brookfield Viscosity (cps) 123,000 - -F~rranti-Shirley Plastic Viscosity ~cps) ~ 434 384 Ferranti-Shirley Yield Value (dynes/cm2) - 7,61~ 7,077 2~C 25C 37C
Brookfield Viscosity (cps) 109,000 ~ ~
Ferranti-Shirley Plastic Viscosity ~cps) - 692 558 Ferranti-Shirley Yield Value (dynes/cm2) - 10,081 11,046 Miosis-time data using 6 albino rabbits is obtained from formu-lations A and B of Table VII and a control formulation of a pilocarpine hydrochloride aqueous solution. The miosis data is set forth herein below in Table IX. Fifty microliter doses were ~iven.
Tabie IX
Control 2~
Pupil Diameter (mm) Pilocarpine Time (Hr) A B Solution 0 4.92 5.06 5.08 ~.5 3,72 3.53 3.~3 1.~ 3.23 3.27 3.55 2.0 3.37 3.32 4.05 3.0 3.57 3.13 ~.63 3.5 3.55 3.38 ~.73 4.5 3.67 3.5$ ~.g8 5.5 3.77 3,77 5.20
6.5 4.00 4.03
7.5 4.47 4.~2
8.5 4.57 4.~0
9 5 _ 4.78
10.5 - 5.12 s~
~ `
EXAMPLE IV
To demons~rate the dependency of ocular retention time on the enhanced duration of the gel compositions of the invention, two studies were conducted and summarized as follows:
a~ Three groups of rabbits, six to a group, were dosed ```
with 50 ul of carboxypolymethylene gel containing 1.7 pilocarpine prepared by method B. Using a saline saturated cotton swab, the gel was removed from two ~roups o rabbit eyes 60 and 120 minutes post instilla~
tion and compared to the control group in which the gel formulation remained in the rabbit eye. The control group of rabbits gave a miosis duration of 8.06 hours; whereas the test groups showed durations of 5.18 and 5.28 hours corresponding to removal of ~el at 60 and 120 minutes 1~ post instillation. Therefore, removal of the gel from rabbit eyes, even after two hours, significantly shortened the duration o~ response.
b~ Tritiated pilocarpine was used to prepare a carboxypoly-methylene pilocarpine salt according to method B.Tritiated pilocarpine ~as also incorporated into petrolatum. Each formulation, containing 1.7% pilocarpine, was dosed in a volume of 50 ul to the right eye of rabbits. Periodically, a group of rabbits, six to a group, were sacrificed. The entire conjunctival sac of each rabbit was excised and the contents of tritiated pilocarpine determined in each.
At two hours post instillation 30% of the pilocarpine/
carboxypolymethylene formulation remained in the rabbit eye; however, the pilocarpine/petrolatum formulation remaining in the rabbit eye was reduced to 30% at only 15 minutes post instillation. Over 60% of the pilocarpine/
petrolatum formulation was removed after five minutes;
-lS-8~3 .
whereas, no pilocarpine/carboxypolymethylene had been removed at this same time period. The retention of the gel formulation was sho~n to be superiox in rabbit eye retention to pe~rolatum which according to Fraunfelder and Hanna (Survey of Ophth., 18, 292, [1974]) is retained better than vehicles containlng methylcellulose or polyvinyl alcohol. The pilocarpine was used partially as a convenient tracer in this study and the retention results could be qualitatively applied to other ophthalmic drugs as well.
~ `
EXAMPLE IV
To demons~rate the dependency of ocular retention time on the enhanced duration of the gel compositions of the invention, two studies were conducted and summarized as follows:
a~ Three groups of rabbits, six to a group, were dosed ```
with 50 ul of carboxypolymethylene gel containing 1.7 pilocarpine prepared by method B. Using a saline saturated cotton swab, the gel was removed from two ~roups o rabbit eyes 60 and 120 minutes post instilla~
tion and compared to the control group in which the gel formulation remained in the rabbit eye. The control group of rabbits gave a miosis duration of 8.06 hours; whereas the test groups showed durations of 5.18 and 5.28 hours corresponding to removal of ~el at 60 and 120 minutes 1~ post instillation. Therefore, removal of the gel from rabbit eyes, even after two hours, significantly shortened the duration o~ response.
b~ Tritiated pilocarpine was used to prepare a carboxypoly-methylene pilocarpine salt according to method B.Tritiated pilocarpine ~as also incorporated into petrolatum. Each formulation, containing 1.7% pilocarpine, was dosed in a volume of 50 ul to the right eye of rabbits. Periodically, a group of rabbits, six to a group, were sacrificed. The entire conjunctival sac of each rabbit was excised and the contents of tritiated pilocarpine determined in each.
At two hours post instillation 30% of the pilocarpine/
carboxypolymethylene formulation remained in the rabbit eye; however, the pilocarpine/petrolatum formulation remaining in the rabbit eye was reduced to 30% at only 15 minutes post instillation. Over 60% of the pilocarpine/
petrolatum formulation was removed after five minutes;
-lS-8~3 .
whereas, no pilocarpine/carboxypolymethylene had been removed at this same time period. The retention of the gel formulation was sho~n to be superiox in rabbit eye retention to pe~rolatum which according to Fraunfelder and Hanna (Survey of Ophth., 18, 292, [1974]) is retained better than vehicles containlng methylcellulose or polyvinyl alcohol. The pilocarpine was used partially as a convenient tracer in this study and the retention results could be qualitatively applied to other ophthalmic drugs as well.
Claims (16)
1. An ophthalmic dosage of an aqueous gel for appli-cation to the conjunctival sac of the eye, said gel comprising an ophthalmic drug and a gel-forming high molecular weight polymer selected from the group consisting of carboxy vinyl polymer and ethylene maleic anhydride, said polymer having a molecular weight in excess of 1,000,000, said ophthalmic drug being present at a level of from about 0.03 to about 15 percent by weight, said polymer being present at a level of from about 2 to about 8 percent by weight, said gel having a viscosity of from about 40,000 to about 300,000 cps and a yield value of from about 5,000 to about 20,000 dyne/cm2.
2. An aqueous gel in accordance with Claim 1 wherein said polymer has a molecular weight of from about 1,000,000 to about 6,000,000.
3. An aqueous gel in accordance with Claim 1 wherein said gel has a viscosity of from about 75,000 to about 200,000 cps.
4. An aqueous gel in accordance with Claim 1 wherein said gel has a viscosity of from about 90,000 to about 150,000 cps .
5. An aqueous gel in accordance with Claim 1 wherein said ophthalmic drug is selected from the group consisting of idoxuridine, pilocarpine and its acceptable salts, and carba-chol.
6. An aqueous gel in accordance with Claim 1 wherein said ophthalmic drug is an ophthalmic steroid selected from the group consisting of hydrocortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate, fluorocinolone, medrysone, prednisolone, methylprednisolone, prednisolone 21-phosphate, prednisolone acetate, fluorometholone, betamethasone and triamcinolone.
7. An aqueous gel in accordance with Claim 1 wherein said ophthalmic drug is an ophthalmic antibiotic selected from the group consisting of neomycin, polymyxin, chloramphenicol, erythromycin, tobramycin, and gentamycin.
8. An aqueous gel in accordance with Claim 1 wherein the pH of said gel is from about 4.5 to about 8.5.
9. An aqueous gel in accordance with Claim 1 wherein said ophthalmic drug is pilocarpine and said high molecular weight polymer is carboxypolymethylene, said gel having a viscosity of from about 75,000 to about 200,000 cps and a yield value of from about 5,000 to about 20,000 dyne/cm2.
10. An ophthalmic drug dosage comprising an anhydrous mixture of an ophthalmic drug and a gel-forming high molecular weight polymer having a molecular weight in excess of 1,000,000 selected from the group consisting of carboxy vinyl polymer and ethylene maleic anhydride, the concentration of said ophthalmic drug and said polymer in said mixture being selected such that when said mixture is introduced into the conjunctival sac of the eye and mixed with the aqueous tear fluid therein an aqueous gel is formed containing between about 0.03 and about 15 percent by weight of said ophthalmic drug and between about 2 and about 8 percent by weight of said polymer, said gel having a viscosity of between about 40,000 and about 300,000 cps and a yield point of between about 5,000 and about 20,000 dynes/cm2.
11. An ophthalmic dosage in accordance with Claim 10 wherein said polymer has a molecular weight of from about 1,000,000 to about 6,000,000.
12. An ophthalmic dosage in accordance with Claim 10 wherein said ophthalmic drug is selected from the group consis-ting of idoxuridine, pilocarpine, and carbachol.
13. An ophthalmic dosage in accordance with Claim 10 wherein said ophthalmic drug is an ophthalmic antibiotic selected from the group consisting of neomycin, polymyxin, chloramphenicol, erythromycin, tobramycin, and gentamycin.
14. An ophthalmic dosage in accordance with Claim 10, wherein said ophthalmic drug is pilocarpine and said high molec-ular weight polymer is carboxypolymethylene.
15. An ophthalmic dosage in accordance with Claim 10, wherein said mixture is suspended in a nonaqueous vehicle.
16. An ophthalmic drug dosage in accordance with Claim 15, wherein said vehicle is a stabilized oil selected from the group consisting of mineral oil, vegetable oil, and silicone fluid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US87207478A | 1978-01-25 | 1978-01-25 | |
| US872,074 | 1978-01-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1108053A true CA1108053A (en) | 1981-09-01 |
Family
ID=25358780
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA318,447A Expired CA1108053A (en) | 1978-01-25 | 1978-12-21 | Sustained release ophthalmic drug dosage |
Country Status (7)
| Country | Link |
|---|---|
| JP (2) | JPS6059885B2 (en) |
| CA (1) | CA1108053A (en) |
| CH (1) | CH640737A5 (en) |
| DE (1) | DE2902863C2 (en) |
| FR (1) | FR2415459A1 (en) |
| GB (1) | GB2013084B (en) |
| MX (1) | MX6520E (en) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3066859D1 (en) | 1979-10-26 | 1984-04-12 | Smith & Nephew Ass | Autoclavable emulsions |
| GB2075837B (en) * | 1980-05-14 | 1984-03-14 | Hisamitsu Pharmaceutical Co | Topical pharmaceutical gel containing anti-inflammatory analgesic agents |
| GB8500310D0 (en) * | 1985-01-07 | 1985-02-13 | Leo Pharm Prod Ltd | Pharmaceutical preparation |
| US6255299B1 (en) | 1985-01-07 | 2001-07-03 | Leo Pharmaceutical Products Ltd. | Opthalmic gel composition and method of treating eye infections |
| US5192535A (en) * | 1988-02-08 | 1993-03-09 | Insite Vision Incorporated | Ophthalmic suspensions |
| US5188826A (en) * | 1988-02-08 | 1993-02-23 | Insite Vision Incorporated | Topical ophthalmic suspensions |
| US5124154A (en) * | 1990-06-12 | 1992-06-23 | Insite Vision Incorporated | Aminosteroids for ophthalmic use |
| JP2873530B2 (en) * | 1991-12-13 | 1999-03-24 | 参天製薬株式会社 | Carboxyvinyl polymer-containing ophthalmic base showing Newtonian viscosity |
| CN1049358C (en) * | 1993-01-01 | 2000-02-16 | 参天制药株式会社 | Carboxybinil polymer which shows newtonian viscosity |
| US5340572A (en) * | 1993-02-08 | 1994-08-23 | Insite Vision Incorporated | Alkaline ophthalmic suspensions |
| EP0748342B1 (en) | 1994-03-04 | 2001-10-04 | University of Washington | Block and graft copolymers and methods relating thereto |
| US5683709A (en) * | 1994-05-05 | 1997-11-04 | Ciba Vision Corporation | Poly(benzalkonium salt) as an anti-microbial agent for aqueous drug compositions |
| DE19614823A1 (en) * | 1996-04-15 | 1997-10-16 | Mann Gerhard Chem Pharm Fab | Ophthalmic composition with prolonged retention time on the eye |
| US6593319B1 (en) | 1999-10-15 | 2003-07-15 | Leo Pharmaceutical Products, Ltd. A/S | Fusidic acid derivatives |
| EP2113246B1 (en) * | 2003-08-07 | 2016-06-22 | Allergan, Inc. | Compositions for delivery of therapeutics into the eyes and methods for making and using the same |
| DE102010009475B4 (en) | 2010-02-26 | 2011-11-24 | F. Holzer Gmbh | Process for the preparation of a dosable ready-to-use preparation |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1012060A (en) * | 1964-10-06 | 1977-06-14 | Gilman N. Cyr | Dimethyl sulfoxide gel preparations |
| FR2038105A1 (en) * | 1969-04-01 | 1971-01-08 | Syntex Corp | Antiinflammatory steroid preparations |
| DK135267A (en) * | 1971-02-25 | |||
| DE2239206A1 (en) * | 1971-08-12 | 1973-03-15 | Hydrophilics Int Inc | COPOLYMER |
| US3957740A (en) * | 1972-04-24 | 1976-05-18 | Hydrophilics International, Inc. | Copolymers |
| FR2191941A1 (en) * | 1972-07-10 | 1974-02-08 | Serabonian Giacomo | Gelatinising water-sol and aq liqs - by addn of carboxypolymer and alginic acid salt |
| DE2265164C3 (en) * | 1972-10-18 | 1985-08-22 | Vsesojuznyj naučno-issledovatel'skij i ispytatel'nyj institut medicinskoj techniki, Moskau/Moskva | Use of acrylic acid amide copolymers for the production of bases for ophthalmic drug forms |
| AR206692A1 (en) * | 1972-12-27 | 1976-08-13 | Alza Corp | DISPENSING AGENT OF SUSTAINED RELEASE OF ACTIVE SUBSTANCES |
| LU70487A1 (en) * | 1974-07-08 | 1976-05-31 | ||
| US4003991A (en) * | 1974-08-27 | 1977-01-18 | National Patent Development Corporation | Ophthalmic formulation |
| JPS5138412A (en) * | 1974-09-24 | 1976-03-31 | Nippon Kayaku Kk | Kokoseizai no seiho |
| IL50250A (en) * | 1975-08-27 | 1980-01-31 | Hydrophilics Int Inc | Sustained release compositions comprising slats of pharmaceutically acitve bases with polymers containing acid groups |
| JPS6056684B2 (en) * | 1977-11-07 | 1985-12-11 | 東興薬品工業株式会社 | eye drops |
-
1978
- 1978-11-23 GB GB7845835A patent/GB2013084B/en not_active Expired
- 1978-12-21 CA CA318,447A patent/CA1108053A/en not_active Expired
-
1979
- 1979-01-12 FR FR7900789A patent/FR2415459A1/en active Granted
- 1979-01-16 JP JP54003844A patent/JPS6059885B2/en not_active Expired
- 1979-01-23 MX MX797677U patent/MX6520E/en unknown
- 1979-01-24 CH CH71879A patent/CH640737A5/en not_active IP Right Cessation
- 1979-01-25 DE DE2902863A patent/DE2902863C2/en not_active Expired - Lifetime
-
1986
- 1986-12-10 JP JP61294588A patent/JPS62215518A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| DE2902863C2 (en) | 1994-02-24 |
| FR2415459B1 (en) | 1983-03-18 |
| JPS62215518A (en) | 1987-09-22 |
| JPH0428244B2 (en) | 1992-05-13 |
| GB2013084A (en) | 1979-08-08 |
| DE2902863A1 (en) | 1979-07-26 |
| JPS54110312A (en) | 1979-08-29 |
| GB2013084B (en) | 1982-07-28 |
| JPS6059885B2 (en) | 1985-12-27 |
| CH640737A5 (en) | 1984-01-31 |
| MX6520E (en) | 1985-06-27 |
| FR2415459A1 (en) | 1979-08-24 |
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