CA1105834A - Ophthalmic preparations and process for producing the same - Google Patents
Ophthalmic preparations and process for producing the sameInfo
- Publication number
- CA1105834A CA1105834A CA312,430A CA312430A CA1105834A CA 1105834 A CA1105834 A CA 1105834A CA 312430 A CA312430 A CA 312430A CA 1105834 A CA1105834 A CA 1105834A
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- Prior art keywords
- gel
- aqueous solution
- viscosity
- centipoises
- added
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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
Abstract
ABSTRACT OF THE DISCLOSURE
The disclosure describes an ophthalmic preparation which is in the form of a gel and which comprises an aqueous solution of a carboxyvinyl polymer, a water-soluble basic sub-stance and an ophthalmic drug admixed with the solution. The gel has a pH of 5 to 8 and a viscosity of 1,000 to 100,000 centi-poises at 20°C. A process of preparing this preparation is also disclosed. The preparation enables the mucous membrane of the eye, the cornea and the like to fully absorb the ophthalmic drug.
The disclosure describes an ophthalmic preparation which is in the form of a gel and which comprises an aqueous solution of a carboxyvinyl polymer, a water-soluble basic sub-stance and an ophthalmic drug admixed with the solution. The gel has a pH of 5 to 8 and a viscosity of 1,000 to 100,000 centi-poises at 20°C. A process of preparing this preparation is also disclosed. The preparation enables the mucous membrane of the eye, the cornea and the like to fully absorb the ophthalmic drug.
Description
1~5834 The present invention relates to novel ophthalmic pre-parations and a process for producing the same.
Eye lotions or ophthalmic ointments have heretofore been widely used as ophthalmic preparations. Eye lotions, which usually contain purified water as the hase ingredient, are not easily spreadable over the cornea or become diluted with the ~ear when applied to the eye, so that a large amount of the lotion falls off the eyelids. Thus difficulties have been encountered in causing the medicinal ingredient of eye lotions to be fully retained on the eyelids or absorbed by the body.
Ophthalmic ointments, which contain vaselineor a mix-ture of vaseline and liquid paraffin or purified lanolin as the base ingredient, are not hydrophilic, are therefore liable to be dislodged from the eyelids and unable to effectively adhere to the cornea and the mucous rnembrane of the eye. Accordingly they have the drawback of failing to fully release the active ingre-dient therefrom, permitting only a small amount thereof to reach the affected part for absorption. Additionally ophthalmic oint-ments have another drawback that the oily base ingredient gives the eyelids an unpleasant feel due to its stickiness when the ointment is applied.
The present inventors carried out intensive research to overcome these drawbacks and to provide highly effective ophthalmic preparations which enable the mucous membr~ne of the eye, the cornea and the like to fully absorb ophthalmic drugs and found that preparations incorporating a carboxyvinyl polymer to afford a specified viscosity produce outstanding effects. Thus this invention has been accomplished.
According to the invention there is provided an ophthalmic preparation in the form of a gel suitable for application to the eye, which comprises a homogeneous mixture of an aqueous solution of a carboxyvinyl polymer, havin~ a il~5834 polymer concentration of 0.05 - 5.0~/O by weight, a water-soluble basic substance, ~odium chloride, and a therapeuti-cally effective amount of an ophthalmic drug, said gel having a pH of 5 to 8 and a viscosity of 1,000 centipoises to 100,000 centipoises at 20C.
According to another aspect of the invention there is provided a process for preparing the ophthalmic pre-paration which comprises a) dissolving or dispersing said ophthalmic drug in said aqueous solution of said polymer, neutralizing said carboxyvinyl polymer with said basic substance to a pH of 5 to 8 and introducing said sodium chloride into the mixture, or b) neutralizing said aqueous carboxyvinyl polymer solution containing 0.05 to 5%, by weight, of said polymer with said basic substance to a pH
of 5 to 8, and introducing said ophthalmic drug and said sodium chloride into the mixture, or c) admixing said ophthalmic drug, aqueous carboxyvinyl polymer and basic sub-: stance to form a mixture having a pH of 5 to 8, and intro-ducing the sodium chloride to said mixture.
Carboxyvinyl polymers useful in this invention are hydrophilic polymers polymerized predominantly from an acrylic acid. Examples of such polymers are those commercially available under the trademarks Carbopol 934, 940 and 941 and manufactured by B. F. Goodrich Chemical Co., U.S.A.
- la .~
S~334 Carboxyvinyl polymers have free carboxy groups.
The aqueou~ ~olution of such a polymer is acidic and ~orms a consistent gel when neutralized with a base. Examples of water-soluble basic substances useful in this invention for neutralizing carboxyvinyl polymers are organic amines includ-ing alkylamines such as methylamine, ethylamine and propyl-amine; dialkylamines such as dimethylamine, diethylamine and dipropylamine; trialkylamines such as trimethylamine, triethylamine and tripropylamine; alkanolamines such as methanolamine, ethanolamine and propanolamine, dialkanol-amines such as dimethanolamine, diethanolamine, dipropanol-amine and dibutanolamine; trialkanolamines such as tri-methanolamine, triethanolamine, tripropanolamine and tri-butanolamine; and trimethylolaminomethane. Inorganic bases such as aqueous solutions of ammonia and alkali hydroxides are also usable. Carboxyvinyl polymers, when neutralized, give gels of substantially the same viscosity irrespective of the kind of the
Eye lotions or ophthalmic ointments have heretofore been widely used as ophthalmic preparations. Eye lotions, which usually contain purified water as the hase ingredient, are not easily spreadable over the cornea or become diluted with the ~ear when applied to the eye, so that a large amount of the lotion falls off the eyelids. Thus difficulties have been encountered in causing the medicinal ingredient of eye lotions to be fully retained on the eyelids or absorbed by the body.
Ophthalmic ointments, which contain vaselineor a mix-ture of vaseline and liquid paraffin or purified lanolin as the base ingredient, are not hydrophilic, are therefore liable to be dislodged from the eyelids and unable to effectively adhere to the cornea and the mucous rnembrane of the eye. Accordingly they have the drawback of failing to fully release the active ingre-dient therefrom, permitting only a small amount thereof to reach the affected part for absorption. Additionally ophthalmic oint-ments have another drawback that the oily base ingredient gives the eyelids an unpleasant feel due to its stickiness when the ointment is applied.
The present inventors carried out intensive research to overcome these drawbacks and to provide highly effective ophthalmic preparations which enable the mucous membr~ne of the eye, the cornea and the like to fully absorb ophthalmic drugs and found that preparations incorporating a carboxyvinyl polymer to afford a specified viscosity produce outstanding effects. Thus this invention has been accomplished.
According to the invention there is provided an ophthalmic preparation in the form of a gel suitable for application to the eye, which comprises a homogeneous mixture of an aqueous solution of a carboxyvinyl polymer, havin~ a il~5834 polymer concentration of 0.05 - 5.0~/O by weight, a water-soluble basic substance, ~odium chloride, and a therapeuti-cally effective amount of an ophthalmic drug, said gel having a pH of 5 to 8 and a viscosity of 1,000 centipoises to 100,000 centipoises at 20C.
According to another aspect of the invention there is provided a process for preparing the ophthalmic pre-paration which comprises a) dissolving or dispersing said ophthalmic drug in said aqueous solution of said polymer, neutralizing said carboxyvinyl polymer with said basic substance to a pH of 5 to 8 and introducing said sodium chloride into the mixture, or b) neutralizing said aqueous carboxyvinyl polymer solution containing 0.05 to 5%, by weight, of said polymer with said basic substance to a pH
of 5 to 8, and introducing said ophthalmic drug and said sodium chloride into the mixture, or c) admixing said ophthalmic drug, aqueous carboxyvinyl polymer and basic sub-: stance to form a mixture having a pH of 5 to 8, and intro-ducing the sodium chloride to said mixture.
Carboxyvinyl polymers useful in this invention are hydrophilic polymers polymerized predominantly from an acrylic acid. Examples of such polymers are those commercially available under the trademarks Carbopol 934, 940 and 941 and manufactured by B. F. Goodrich Chemical Co., U.S.A.
- la .~
S~334 Carboxyvinyl polymers have free carboxy groups.
The aqueou~ ~olution of such a polymer is acidic and ~orms a consistent gel when neutralized with a base. Examples of water-soluble basic substances useful in this invention for neutralizing carboxyvinyl polymers are organic amines includ-ing alkylamines such as methylamine, ethylamine and propyl-amine; dialkylamines such as dimethylamine, diethylamine and dipropylamine; trialkylamines such as trimethylamine, triethylamine and tripropylamine; alkanolamines such as methanolamine, ethanolamine and propanolamine, dialkanol-amines such as dimethanolamine, diethanolamine, dipropanol-amine and dibutanolamine; trialkanolamines such as tri-methanolamine, triethanolamine, tripropanolamine and tri-butanolamine; and trimethylolaminomethane. Inorganic bases such as aqueous solutions of ammonia and alkali hydroxides are also usable. Carboxyvinyl polymers, when neutralized, give gels of substantially the same viscosity irrespective of the kind of the
-2-. . .
basic substance used.
Preferably, the neutralization of carboxyvinyl polymers with water-soluble basic substances is generally so adjusted that the resulting preparation in the form of a gel has a pH close to neutrality, i.e. of 5 to 8. It is desired that the preparation have a pH value which is most favorable to the stability of the drug to be incorporated therein. Accordingly the gel prepara-tion of this invention should be adjusted to a pH o~ 5 to 8.
According to this invention, ophthalmic drugs are us-able whether they are soluble or insoluble in water. Water-insoluble drugs, when used, render the resulting gel preparation turbid but will not precipitate in the preparation, so that the preparation is applicable without any trouble. However, an auxi-liary dissolving agent may be used to render the preparation transparent or more effectively absorbable by the body. Alter-natively the ophthalmic drug may be dissolved in a water-soluble organic solvent first and then formulated into a preparation.
Examples of such water-soluble organic solvents are propylene glycol, polyethylene glycol having a molecular weight of 300 to 400, etc., among which propylene glycol, which is widely usable, is suitable. Furthermore, water-soluble basic substances may be used also as solvents. Examples of auxiliary dissolving agents are nonionic sur~actants including fatty acid esters of polyoxy-ethylene sorbitan such as polyoxyethylene sorbitan monopalmitate and polyoxyethylene sorbitan monostearate, polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether, polyoxyethylene cetyl ethër, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether and polyoxyethylene behenyl ether; and ben7,yl alcohol.
Ophthalmic drugs useful in this invention are those nonionic and stable in preparations, namely in aqueous media.
Examples of ophthalmic drugs suitable for use in the gel prepara-tions of this invention are prednisolone, cortisone~ hydrocorti~
1~5834 sone, hydrocortisone acetate, methylprednisolone, cortisone ace-tate, cortisone caproate, dexamethasone, betamethasone, betame-thasone valerate, betamethasone benzoate, dexamethasone acetate, dexamethasone valerate, flumethasone, fluocinolone acetonide, fluocinonide, flumethasone, prednisolone acetate, methylpredni-solone acetate, triamcinolone, triamcinolone acetonide and like adrenocortical hormones and derivatives thereof, chloramphenicol, tetracycline, oxytetracycline, chlortetracycline, penicillin and like antibiotics, vitamin B2, vitamin B6, vitamin B12, vitamin A, vitamin E, vitamin D and like vitamins, boric acid, acrinol, azulene, flavin adenine dinucleotide, allantoin, glutathione, sulfa drugs, etc.
- According to the process of this invention, prepara-: tions in the form of a gel are produced by dissolving or disper-sing an ophthalmic drug in an aqueou3 carboxyvinyl polymer solu-tion and uniformly mixing the.solution or dispersion with a water-soluble basic substance which is added to the solution while stirring to afford an adjusted pH of 5 to 8, or by admixing a water-soluble basic substance with an aqueous carboxyvinyl poly-mer solution while stirring to obtain a gel and adding an ophthal-mic drug to the gel. The gel preparations obtained have a vis-cosity of 1,000 to 100,000 centipoises at 20 C. Gels having a iSCoQity of less than 1,000 centipoises are highly flowable like conventional aqueous eye lotions and wi~l flow out of the body as such or associated with the tear when applied, hence they are undesirable. If the viscosity e~ceeds 100,000 centipoises the : gels are too hard and are not fully collapsible when applied to the mucous membrane of the eye, thus involving difficulties in ~: the release of the ophthalmic drug from the gel, adsorption of ~:, :~ 30 the drug by the mucous membrane and absorption of-the drug by the `. body.
. The gel preparations of this invention have a viscosity 5~34 widely ranging from 1,000 centipoises to 100,000 centipoises.
Preparations with a relatively low viscosity of from about 1,000 to about 10,000 centipoises have good flowability and ~an be applied dropwise directly onto the mucous membrane around the eyeball. On the other hand, relatively viscous preparations having a viscosity of about 10,000 to about 100,000 centipoises are less flowable, pasty and consistent than ointments and can therefore be applied to the eyelids like conventional-ophthalmic ointments to obtain medicinal results.
When the ophthalmic preparations of this invention are used, the tear collapses the gel to a liquid which can be readily adsorbed by the mucous membrane and the cornea. Even viscous gels turn to a liquid on application owing to a rapid reduction in viscosity, so that the ophthalmic drug contained in the gel will be absorbed by the mucous membrane of the eye and the cornPa in intimate contact therewith. Whereas conventional eye lotions are likely to be carried away with the tear, the preparations of this invention are in the form of a gel, which breaks down to assure the adsorption of the ophthalmic drug on the mucous mem-brane of the eye or the like. Accordingly the preparations can produce sufficient medicinal effects without being carried along as such by the tear. Conventional ophthalmic ointments, which contain vaseline, lanolin or like oleophilic base ingredient, will not intimately attach to the mucous membrane of the eye, are very likely to be carried away by the tear without allowing sufficient absorption of the ophthalmic drug and give a sticky and uncomfor-table feel to the eyelids. In contrast, the ophthalmic prepara-tion of this invention, even when viscous, can be very easily converted by the tear to a liquid which intimate~y attaches to the membrane. Moreover the present preparations give no dis-comfort to the patient since they are free from any oleophilic base ingredient. With gel preparations of low viscosity, the mucous membrane of the eye intimately adsorbs and absorbs the ophthalmic drug rapidly, while the gel takes a longer time for breakdown with an încrease in viscosity, resulting in moderate absorption of the drug and affording a sustained medicinal effect.
For this reason, a gel preparation of relatively low viscosity is preferable when it is desired to rapidly achieve a medicinal effect through efficient adsorption on the mucous membrane, where-as a sustained effect is available for a prolonged period of time with a gel preparation of relatively high viscosity. The visco-10 sity, although somewhat dependent on the drug used, is governed mainly by the concentration of the carboxyvinyl polymer. For the formulation of gel preparations of specified viscosity, the car-boxyvinyl polymer is used in the form of an aqueous solution having a concentration of O.OS to 5.0% by weight. When the addi-tion of some ophthalmic dru~ leads to a reduced viscosity, the desired viscosity can be obtained with the use of an aqueous solu-~ tion containin~ an increased amount of carboxyvinyl polymer.
S The preparation of this invention, when applied to the eye, undergoes a marked reduction in its viscosity with break~
20 down of its gel form, presumably due to the presence of sodium chloride in the tear. We found that the addition of a small a-mount of sodium chloride or an aqueous solution thereof to the ophthalmic preparation of this invention converts the gel to a liquid with a great reduction of its viscosity. Directing atten-tion to this finding, we conducted further research, which has revealed that the addition of a small amount of sodium chloride to the ophthalmic preparations of this invention delays the break-.~ ~
-~ down of the gel when the preparation is applied to the mucous ~-~ membrane of the eye. Thus ophthalmic preparations containing so-dium chloride are suitable when sustained effects are desirable.
;- In this case, it is preferable to use an increased amount of car-boxyvinyl polymer to compensate for the reduction of viscosity , . . .
due to the addition of sodium chloride.
Although dependent on the kind of ophthalmic drug in-corporated, the preparations of this invention, when containing steroids or antibiotics for example, are remarkably effective for the curing of various inflammatory diseases such as kerati-tis, scleritis, blepharitis and iridocyclitis. They are also useful for asthenopia (fatigue of the eyes), conjunctival injec-tion (bloodshot eyes), prevention of ophthalmic diseases (after swimming or when dust or perspiration has ingressed into the eye~, inflammation of the eyes (snow blindness) caused by exposure to ultraviolet rays or other rays! dacryocystitis (teary eyes), in-flammation of eyelids (bleary eye), bacterial conjunctivitis, replenishment of the tear and various other applications.
Given below are Examples of this invention, in which the viscosities were measured at 20 C by a C-type viscosimeter produced by Tokyo Keiki Co., Ltd., Japan.
Example 1 One gram of carboxyvinyl polymer (Carbopol 940) was dissolved in 99 g of sterilized purified water to prepare a 1%
aqueous solution of carboxyvinyl polymer.
To 7.5 g of the 1% aqueous solution of carboxyvinyl polymer there were added 90.5 g of sterilized purified water, and 1.5 g of a solution prepared by dissolving 2 g of sodium hydro-xide in 98 g of sterilized purified water was slowly added to the mixture with full stirring. With continued stirring, the solution became a gel, to which 0.5 g of chloramphenicol powder was added. The mixture was vigorously stirred to give a prepara-tion in the form of a gel containing 0~5% of chloramphenicol uni-formly dispersed therein and having a pH of 7.0 and a viscosity of 2,000 centipoises.
Example 2 To a mixture of 20 g of a 4% aqueous solution of car~o-1~35i~33~
xyvinyl polymer and 74.8 g of sterilized purified water, 3.2 gof 10% aqueous solution of sodium hydroxide were added while stirring. When thoroughly stirred, the mixture gave a consistent gel, to which 2 g of chloramphenicol powder was added. The re-sulting mixture was vigorously stirred, giving a gel preparation containing 2% of chloramphenicol and having a pH of 6.95 and a viscosity of 40,000 centipoises.
Example 3 Ten grams of a 1% aqueous ~olution of carboxyvinyl po-lymer was added to an aqueous solution of 0.02 g of water-soluble azulene (active component ofchamomile flower) in 87.98 g of sterilized purified water. To the mixture, 2.0 g of 2% aqueous colution of sodium hydroxide were added while stirring to produce a gel preparation having a pH of 7.00 and a viscosity of 4,000 centipoises.
Example 4 A 0.05 g quantity of acrinol was dissolved in ~2.79 g of sterilized purified water while heating on a water bath, and the solution was cooled. To the solution, 14.3 g of a 1% aqueous solution of carboxyvinyl polymer were added, and the mixture was stirred. Subsequently 2.86 g of a 2% aqueous solution of sodium hydroxide was added to the mixture. The resulting mixture was thoroughly stirred, giving a gel preparation having a pH of 6.50 and a viscosity of 3,000 centipoises.
Example 5 2 g of boric acid were dissolved in 80.84 g of steri-, lizedpurified water while heating on a water bath, and the solu-tion was cooled. To this solution, 14.3 g of a 1% aqueous solu-tion of carboxyvinyl pol~er were added and the mixture was stirred. And then, 2.86 g of a 2% aqueous solution of sodium hydroxide were added to the mixture. The resulting mixture was thoroughly stirred, giving a gel preparation having a pH of 6.50 and a viscosity of 3,000 centipoises.
Example 6 To 20 g of propylene glycol heated to about 70C on a water bath, 0.05 g of butyric acid ester of riboflavin was dis-solved, and the resulting solution was cooled. To this solution, there were added 67.09 g of sterilized purified water and 10 g of a 1% aqueous solution of carboxyvinyl polymer and the mixture was thoroughly stirred. And then, 2.86 g of aqueous solution of sodium hydroxide were added to the mixture. The resulting mix-ture was thoroughly stirred, giving a gel preparation having a pH of 80 00 and a viscosity of 5,000 centipoises.
Example 7 To 20 g of propylene glycol heated to about 70C on a water bath, 0.1 g of butyric acid ester of riboflavin was dis-solved, and the resulting solution was cooled. To this solution, there were added 50.9 g of sterilized purified water, 25 g of 4%
aqueous solution of carboxyvinyl polymer and 4 g of 10% aqueous solution of sodium hydroxide, and the resulting mixture was thoroughly stirred to give a gel preparation having a pH of 6.99 20 and a viscosity of 50,000 centipoises.
Example 8 ~o 25 g of propylene glycol heated to about 90C on a water bath, 0.5 g of prednisolone was dissolved, and 60.1 g of sterilized purified water and 12 g of 1% aqueous solution of car-boxyvinyl polymer were added to the above solution. To the mix-ture, 2.4 g of sodium hydroxide were added while stirring to give a gel preparation having a pH of 7.10 and a viscosity of 2,200 centipoises.
Example 9 Into 20 g of propylene glycol heated to about 90C on a water bath, 0.5 g of prednisolone was dissolved, and 50.5 g of sterilized purified water and 25 g of 4% aqueous solution of car-1~583~
boxyvinyl polymer were added to th~ above solution. To the mix-ture, 4 g of a 10% aqueous solution of sodium hydroxide were added while stirring to give a gel preparation having a pH of 6.80 and a viscosity of 43,000 centipoises.
E~ample 10 To 25 g of propylene glycol heated to about 90C on a water bath, 0.5 g of hydrocortisone was dissolved, and 60.1 g of sterilized purified water and 12 g of 1% aqueous solution of carboxyvinyl polymer were added to the above solution while stir-ring. To the mixture, 2.4 g of a 2% aqueous solution of sodium hydroxide were added while stirring to give a gel preparation having a pH of 7.10 and a viscosity of 2,200 centipoises.
Example 11 To 20 g of propylene glycol heated to about 90C on a water bath, 0.5 g of hydrocortisone was dissolved and 50.5 g of sterilized purified water and 25 g of 4% aqueous solution of car-boxyvin~l polymer were added to the above solution while stirring.
To this mixture, 4 g of a 10% aqueous solution of sodium hydro-xide were added while stirring to give a gel preparation having 20 a pH of 6.80 and a viscosity of 42,000 centipoises.
Example 12 ~o 25 g of propylene glycol heated to about 90C on a water bath, 0.1 g of dexamethasone was dissolved, and 60.5 g of sterilized purified water and 12 g of a 1% aqueous solution of carboxyvinyl polymer were added to the above solution while stir-ring. To the mixture, 2.4 g of a 2% aqueous solution of sodium hydroxide were added while stirring to give a gel preparation having a pH of 7.05 and a viscosity of 2,200 centipoises.
Example 13 0.1 g of allantoin was dissolved in 76.7 g of steri-lized purified water while heating gently, and to this solution, 20 g of a 4% aqueou~ aolution of carboxyvinyl polymer and 3.2 g ~S834 of 10% aqueous solution of sodium hydroxide were added while stirring, to give a gel preparation having a pH of 6.95 and a viscosity of 40,000 centipoises.
Example 14 0.1 g of allantoin was dissolved in 90.9 g of steril~ed purified water while heating gently, and to this solution, 7.5 g of 2 1% aqueous solution of carboxyvinyl polymer and 1.5 g of a 2% aqueous solution of sodium hydroxide were added while stir-ring to give a gel preparation having a pH of 7.00 and a visco-sity of 2,000 centipoises.
Example 15 To 20 g of propylene glycol heated to about 70~C on a water bath, 0.05 g of flavin-adenin-dinucleotide was dissolved and the resulting solution was cooled. To this solution, 67.09 g of sterilized purified water and 10 g of a 1% aqueous solution of carboxyvinyl polymer were added while stirring. To this mix-ture, 2.86 g of a 2% aqueous solution of sodium hydroxide were added while stirring to give a gel preparation having a pH of 7.00 and a viscosity of 5,000 centipoises.
Example 16 To 20 g of propylene glycol heated to about 70C on a water bath, 0.1 g of flavin-adenin-dinucleotide was dissolved, and the resulting solution was cooled. To this solution, 50.9 g of sterilized purified water and 25 g of a 4% aqueous solution of carboxyvinyl polymer were added while stirring. To this mix-ture, 4 g of a 10% aqueous solution of sodium hydroxide were added while stirring to give a gel preparation having a p~ of 6.99 and a viscosity of 50,000 centipoises.
Example 17 ~.0 g of boric acid were dissolved in 64.4 g of steri-lized purified water while heating gently. After cooling, 12 g of a 4% aqueous solution of carboxyvinyl polymer were added to ~583~
the above solution while stirring. To this mixture, 9.6 g of a 2% aqueous solution of sodium hydroxide were added in small por-tions to give a gel preparation having a pH of 6.90 and a visco-sity of 30,000 centipoises.
To the above gel, 12 g of a 1% aqueous solution of so-dium chloride were added in small portions while stirring. The viscosity of the gel was dropped. After stirring thoroughly, a gel preparation having a pH of 7.00 and a viscosity of 3,000 cen-tipoises was obtained.
Example 18 To 25 g of propylene glycol heated to about 90C on a water bath, 0. 5 g of prednisolone was dissolved, and to the re-sulting solution 43 g of sterilized purified water and 11.5 g of 4% aqueous solution of carboxyvinyl polymer were added while stirring. To this solution, 8 g of a 2% aqueous solut on of so-dium hydroxide were added while stirring. A uniform gel having a pH of 6.90 and a viscosity of 33,000 centipoises was obtained.
Subsequently, 12 g of a 1% aqueous solution of sodium chloride were added in small portions to the above gel while 20 stir~ing to give a uniform gel preparation having a pH of 7.00 and a viscosity of 2,200 centipoises.
Example 19 To 61.7 g of sterilized purified water, 11 g of a 4%
carboxyvinyl polymer were added while stirring, and subsequently 8.8 g of a 2% aqueous solution of sodium hydroxide were added in small portions while thoroughly stirring to give a ~el base hav-iny a pH of 6.90 and a viscosity of 29~ 000 centipoises.
To the above gel base, 18 g of a 1% aqueous solution of sodium chloride were added in small portions while stirring.
The viscosity of the gel base started to drop markedly by the addition of an aqueous solution of sodium chloride. 0.5 g of chloramphenicol powder was added to the above gel while stirring 33~
to give a uniform gel preparation having a pH of 7.00 and a vis-cosity of 2,000 centipoises.
Examele 20 0.02 g of ~ater-soluble azulene was dissolved in 47.28 g of sterilized water, and to this solution, 11 g of a 4% aqueous solution of carboxyvinyl polymer were added while stirring, and then, 29.7 g of a 2% aqueous solution of triethanolamine were added in small portions while stirring to give a uniform gel hav-ing a pH of 6.90 and a viscosity of 28,000 centipoises.
12 g of an aqueous solution of sodium chloride were added to the above gel in small portions while stirring, to give a uniform gel preparation having a pH of 7.00 and a viscosity of
basic substance used.
Preferably, the neutralization of carboxyvinyl polymers with water-soluble basic substances is generally so adjusted that the resulting preparation in the form of a gel has a pH close to neutrality, i.e. of 5 to 8. It is desired that the preparation have a pH value which is most favorable to the stability of the drug to be incorporated therein. Accordingly the gel prepara-tion of this invention should be adjusted to a pH o~ 5 to 8.
According to this invention, ophthalmic drugs are us-able whether they are soluble or insoluble in water. Water-insoluble drugs, when used, render the resulting gel preparation turbid but will not precipitate in the preparation, so that the preparation is applicable without any trouble. However, an auxi-liary dissolving agent may be used to render the preparation transparent or more effectively absorbable by the body. Alter-natively the ophthalmic drug may be dissolved in a water-soluble organic solvent first and then formulated into a preparation.
Examples of such water-soluble organic solvents are propylene glycol, polyethylene glycol having a molecular weight of 300 to 400, etc., among which propylene glycol, which is widely usable, is suitable. Furthermore, water-soluble basic substances may be used also as solvents. Examples of auxiliary dissolving agents are nonionic sur~actants including fatty acid esters of polyoxy-ethylene sorbitan such as polyoxyethylene sorbitan monopalmitate and polyoxyethylene sorbitan monostearate, polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether, polyoxyethylene cetyl ethër, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether and polyoxyethylene behenyl ether; and ben7,yl alcohol.
Ophthalmic drugs useful in this invention are those nonionic and stable in preparations, namely in aqueous media.
Examples of ophthalmic drugs suitable for use in the gel prepara-tions of this invention are prednisolone, cortisone~ hydrocorti~
1~5834 sone, hydrocortisone acetate, methylprednisolone, cortisone ace-tate, cortisone caproate, dexamethasone, betamethasone, betame-thasone valerate, betamethasone benzoate, dexamethasone acetate, dexamethasone valerate, flumethasone, fluocinolone acetonide, fluocinonide, flumethasone, prednisolone acetate, methylpredni-solone acetate, triamcinolone, triamcinolone acetonide and like adrenocortical hormones and derivatives thereof, chloramphenicol, tetracycline, oxytetracycline, chlortetracycline, penicillin and like antibiotics, vitamin B2, vitamin B6, vitamin B12, vitamin A, vitamin E, vitamin D and like vitamins, boric acid, acrinol, azulene, flavin adenine dinucleotide, allantoin, glutathione, sulfa drugs, etc.
- According to the process of this invention, prepara-: tions in the form of a gel are produced by dissolving or disper-sing an ophthalmic drug in an aqueou3 carboxyvinyl polymer solu-tion and uniformly mixing the.solution or dispersion with a water-soluble basic substance which is added to the solution while stirring to afford an adjusted pH of 5 to 8, or by admixing a water-soluble basic substance with an aqueous carboxyvinyl poly-mer solution while stirring to obtain a gel and adding an ophthal-mic drug to the gel. The gel preparations obtained have a vis-cosity of 1,000 to 100,000 centipoises at 20 C. Gels having a iSCoQity of less than 1,000 centipoises are highly flowable like conventional aqueous eye lotions and wi~l flow out of the body as such or associated with the tear when applied, hence they are undesirable. If the viscosity e~ceeds 100,000 centipoises the : gels are too hard and are not fully collapsible when applied to the mucous membrane of the eye, thus involving difficulties in ~: the release of the ophthalmic drug from the gel, adsorption of ~:, :~ 30 the drug by the mucous membrane and absorption of-the drug by the `. body.
. The gel preparations of this invention have a viscosity 5~34 widely ranging from 1,000 centipoises to 100,000 centipoises.
Preparations with a relatively low viscosity of from about 1,000 to about 10,000 centipoises have good flowability and ~an be applied dropwise directly onto the mucous membrane around the eyeball. On the other hand, relatively viscous preparations having a viscosity of about 10,000 to about 100,000 centipoises are less flowable, pasty and consistent than ointments and can therefore be applied to the eyelids like conventional-ophthalmic ointments to obtain medicinal results.
When the ophthalmic preparations of this invention are used, the tear collapses the gel to a liquid which can be readily adsorbed by the mucous membrane and the cornea. Even viscous gels turn to a liquid on application owing to a rapid reduction in viscosity, so that the ophthalmic drug contained in the gel will be absorbed by the mucous membrane of the eye and the cornPa in intimate contact therewith. Whereas conventional eye lotions are likely to be carried away with the tear, the preparations of this invention are in the form of a gel, which breaks down to assure the adsorption of the ophthalmic drug on the mucous mem-brane of the eye or the like. Accordingly the preparations can produce sufficient medicinal effects without being carried along as such by the tear. Conventional ophthalmic ointments, which contain vaseline, lanolin or like oleophilic base ingredient, will not intimately attach to the mucous membrane of the eye, are very likely to be carried away by the tear without allowing sufficient absorption of the ophthalmic drug and give a sticky and uncomfor-table feel to the eyelids. In contrast, the ophthalmic prepara-tion of this invention, even when viscous, can be very easily converted by the tear to a liquid which intimate~y attaches to the membrane. Moreover the present preparations give no dis-comfort to the patient since they are free from any oleophilic base ingredient. With gel preparations of low viscosity, the mucous membrane of the eye intimately adsorbs and absorbs the ophthalmic drug rapidly, while the gel takes a longer time for breakdown with an încrease in viscosity, resulting in moderate absorption of the drug and affording a sustained medicinal effect.
For this reason, a gel preparation of relatively low viscosity is preferable when it is desired to rapidly achieve a medicinal effect through efficient adsorption on the mucous membrane, where-as a sustained effect is available for a prolonged period of time with a gel preparation of relatively high viscosity. The visco-10 sity, although somewhat dependent on the drug used, is governed mainly by the concentration of the carboxyvinyl polymer. For the formulation of gel preparations of specified viscosity, the car-boxyvinyl polymer is used in the form of an aqueous solution having a concentration of O.OS to 5.0% by weight. When the addi-tion of some ophthalmic dru~ leads to a reduced viscosity, the desired viscosity can be obtained with the use of an aqueous solu-~ tion containin~ an increased amount of carboxyvinyl polymer.
S The preparation of this invention, when applied to the eye, undergoes a marked reduction in its viscosity with break~
20 down of its gel form, presumably due to the presence of sodium chloride in the tear. We found that the addition of a small a-mount of sodium chloride or an aqueous solution thereof to the ophthalmic preparation of this invention converts the gel to a liquid with a great reduction of its viscosity. Directing atten-tion to this finding, we conducted further research, which has revealed that the addition of a small amount of sodium chloride to the ophthalmic preparations of this invention delays the break-.~ ~
-~ down of the gel when the preparation is applied to the mucous ~-~ membrane of the eye. Thus ophthalmic preparations containing so-dium chloride are suitable when sustained effects are desirable.
;- In this case, it is preferable to use an increased amount of car-boxyvinyl polymer to compensate for the reduction of viscosity , . . .
due to the addition of sodium chloride.
Although dependent on the kind of ophthalmic drug in-corporated, the preparations of this invention, when containing steroids or antibiotics for example, are remarkably effective for the curing of various inflammatory diseases such as kerati-tis, scleritis, blepharitis and iridocyclitis. They are also useful for asthenopia (fatigue of the eyes), conjunctival injec-tion (bloodshot eyes), prevention of ophthalmic diseases (after swimming or when dust or perspiration has ingressed into the eye~, inflammation of the eyes (snow blindness) caused by exposure to ultraviolet rays or other rays! dacryocystitis (teary eyes), in-flammation of eyelids (bleary eye), bacterial conjunctivitis, replenishment of the tear and various other applications.
Given below are Examples of this invention, in which the viscosities were measured at 20 C by a C-type viscosimeter produced by Tokyo Keiki Co., Ltd., Japan.
Example 1 One gram of carboxyvinyl polymer (Carbopol 940) was dissolved in 99 g of sterilized purified water to prepare a 1%
aqueous solution of carboxyvinyl polymer.
To 7.5 g of the 1% aqueous solution of carboxyvinyl polymer there were added 90.5 g of sterilized purified water, and 1.5 g of a solution prepared by dissolving 2 g of sodium hydro-xide in 98 g of sterilized purified water was slowly added to the mixture with full stirring. With continued stirring, the solution became a gel, to which 0.5 g of chloramphenicol powder was added. The mixture was vigorously stirred to give a prepara-tion in the form of a gel containing 0~5% of chloramphenicol uni-formly dispersed therein and having a pH of 7.0 and a viscosity of 2,000 centipoises.
Example 2 To a mixture of 20 g of a 4% aqueous solution of car~o-1~35i~33~
xyvinyl polymer and 74.8 g of sterilized purified water, 3.2 gof 10% aqueous solution of sodium hydroxide were added while stirring. When thoroughly stirred, the mixture gave a consistent gel, to which 2 g of chloramphenicol powder was added. The re-sulting mixture was vigorously stirred, giving a gel preparation containing 2% of chloramphenicol and having a pH of 6.95 and a viscosity of 40,000 centipoises.
Example 3 Ten grams of a 1% aqueous ~olution of carboxyvinyl po-lymer was added to an aqueous solution of 0.02 g of water-soluble azulene (active component ofchamomile flower) in 87.98 g of sterilized purified water. To the mixture, 2.0 g of 2% aqueous colution of sodium hydroxide were added while stirring to produce a gel preparation having a pH of 7.00 and a viscosity of 4,000 centipoises.
Example 4 A 0.05 g quantity of acrinol was dissolved in ~2.79 g of sterilized purified water while heating on a water bath, and the solution was cooled. To the solution, 14.3 g of a 1% aqueous solution of carboxyvinyl polymer were added, and the mixture was stirred. Subsequently 2.86 g of a 2% aqueous solution of sodium hydroxide was added to the mixture. The resulting mixture was thoroughly stirred, giving a gel preparation having a pH of 6.50 and a viscosity of 3,000 centipoises.
Example 5 2 g of boric acid were dissolved in 80.84 g of steri-, lizedpurified water while heating on a water bath, and the solu-tion was cooled. To this solution, 14.3 g of a 1% aqueous solu-tion of carboxyvinyl pol~er were added and the mixture was stirred. And then, 2.86 g of a 2% aqueous solution of sodium hydroxide were added to the mixture. The resulting mixture was thoroughly stirred, giving a gel preparation having a pH of 6.50 and a viscosity of 3,000 centipoises.
Example 6 To 20 g of propylene glycol heated to about 70C on a water bath, 0.05 g of butyric acid ester of riboflavin was dis-solved, and the resulting solution was cooled. To this solution, there were added 67.09 g of sterilized purified water and 10 g of a 1% aqueous solution of carboxyvinyl polymer and the mixture was thoroughly stirred. And then, 2.86 g of aqueous solution of sodium hydroxide were added to the mixture. The resulting mix-ture was thoroughly stirred, giving a gel preparation having a pH of 80 00 and a viscosity of 5,000 centipoises.
Example 7 To 20 g of propylene glycol heated to about 70C on a water bath, 0.1 g of butyric acid ester of riboflavin was dis-solved, and the resulting solution was cooled. To this solution, there were added 50.9 g of sterilized purified water, 25 g of 4%
aqueous solution of carboxyvinyl polymer and 4 g of 10% aqueous solution of sodium hydroxide, and the resulting mixture was thoroughly stirred to give a gel preparation having a pH of 6.99 20 and a viscosity of 50,000 centipoises.
Example 8 ~o 25 g of propylene glycol heated to about 90C on a water bath, 0.5 g of prednisolone was dissolved, and 60.1 g of sterilized purified water and 12 g of 1% aqueous solution of car-boxyvinyl polymer were added to the above solution. To the mix-ture, 2.4 g of sodium hydroxide were added while stirring to give a gel preparation having a pH of 7.10 and a viscosity of 2,200 centipoises.
Example 9 Into 20 g of propylene glycol heated to about 90C on a water bath, 0.5 g of prednisolone was dissolved, and 50.5 g of sterilized purified water and 25 g of 4% aqueous solution of car-1~583~
boxyvinyl polymer were added to th~ above solution. To the mix-ture, 4 g of a 10% aqueous solution of sodium hydroxide were added while stirring to give a gel preparation having a pH of 6.80 and a viscosity of 43,000 centipoises.
E~ample 10 To 25 g of propylene glycol heated to about 90C on a water bath, 0.5 g of hydrocortisone was dissolved, and 60.1 g of sterilized purified water and 12 g of 1% aqueous solution of carboxyvinyl polymer were added to the above solution while stir-ring. To the mixture, 2.4 g of a 2% aqueous solution of sodium hydroxide were added while stirring to give a gel preparation having a pH of 7.10 and a viscosity of 2,200 centipoises.
Example 11 To 20 g of propylene glycol heated to about 90C on a water bath, 0.5 g of hydrocortisone was dissolved and 50.5 g of sterilized purified water and 25 g of 4% aqueous solution of car-boxyvin~l polymer were added to the above solution while stirring.
To this mixture, 4 g of a 10% aqueous solution of sodium hydro-xide were added while stirring to give a gel preparation having 20 a pH of 6.80 and a viscosity of 42,000 centipoises.
Example 12 ~o 25 g of propylene glycol heated to about 90C on a water bath, 0.1 g of dexamethasone was dissolved, and 60.5 g of sterilized purified water and 12 g of a 1% aqueous solution of carboxyvinyl polymer were added to the above solution while stir-ring. To the mixture, 2.4 g of a 2% aqueous solution of sodium hydroxide were added while stirring to give a gel preparation having a pH of 7.05 and a viscosity of 2,200 centipoises.
Example 13 0.1 g of allantoin was dissolved in 76.7 g of steri-lized purified water while heating gently, and to this solution, 20 g of a 4% aqueou~ aolution of carboxyvinyl polymer and 3.2 g ~S834 of 10% aqueous solution of sodium hydroxide were added while stirring, to give a gel preparation having a pH of 6.95 and a viscosity of 40,000 centipoises.
Example 14 0.1 g of allantoin was dissolved in 90.9 g of steril~ed purified water while heating gently, and to this solution, 7.5 g of 2 1% aqueous solution of carboxyvinyl polymer and 1.5 g of a 2% aqueous solution of sodium hydroxide were added while stir-ring to give a gel preparation having a pH of 7.00 and a visco-sity of 2,000 centipoises.
Example 15 To 20 g of propylene glycol heated to about 70~C on a water bath, 0.05 g of flavin-adenin-dinucleotide was dissolved and the resulting solution was cooled. To this solution, 67.09 g of sterilized purified water and 10 g of a 1% aqueous solution of carboxyvinyl polymer were added while stirring. To this mix-ture, 2.86 g of a 2% aqueous solution of sodium hydroxide were added while stirring to give a gel preparation having a pH of 7.00 and a viscosity of 5,000 centipoises.
Example 16 To 20 g of propylene glycol heated to about 70C on a water bath, 0.1 g of flavin-adenin-dinucleotide was dissolved, and the resulting solution was cooled. To this solution, 50.9 g of sterilized purified water and 25 g of a 4% aqueous solution of carboxyvinyl polymer were added while stirring. To this mix-ture, 4 g of a 10% aqueous solution of sodium hydroxide were added while stirring to give a gel preparation having a p~ of 6.99 and a viscosity of 50,000 centipoises.
Example 17 ~.0 g of boric acid were dissolved in 64.4 g of steri-lized purified water while heating gently. After cooling, 12 g of a 4% aqueous solution of carboxyvinyl polymer were added to ~583~
the above solution while stirring. To this mixture, 9.6 g of a 2% aqueous solution of sodium hydroxide were added in small por-tions to give a gel preparation having a pH of 6.90 and a visco-sity of 30,000 centipoises.
To the above gel, 12 g of a 1% aqueous solution of so-dium chloride were added in small portions while stirring. The viscosity of the gel was dropped. After stirring thoroughly, a gel preparation having a pH of 7.00 and a viscosity of 3,000 cen-tipoises was obtained.
Example 18 To 25 g of propylene glycol heated to about 90C on a water bath, 0. 5 g of prednisolone was dissolved, and to the re-sulting solution 43 g of sterilized purified water and 11.5 g of 4% aqueous solution of carboxyvinyl polymer were added while stirring. To this solution, 8 g of a 2% aqueous solut on of so-dium hydroxide were added while stirring. A uniform gel having a pH of 6.90 and a viscosity of 33,000 centipoises was obtained.
Subsequently, 12 g of a 1% aqueous solution of sodium chloride were added in small portions to the above gel while 20 stir~ing to give a uniform gel preparation having a pH of 7.00 and a viscosity of 2,200 centipoises.
Example 19 To 61.7 g of sterilized purified water, 11 g of a 4%
carboxyvinyl polymer were added while stirring, and subsequently 8.8 g of a 2% aqueous solution of sodium hydroxide were added in small portions while thoroughly stirring to give a ~el base hav-iny a pH of 6.90 and a viscosity of 29~ 000 centipoises.
To the above gel base, 18 g of a 1% aqueous solution of sodium chloride were added in small portions while stirring.
The viscosity of the gel base started to drop markedly by the addition of an aqueous solution of sodium chloride. 0.5 g of chloramphenicol powder was added to the above gel while stirring 33~
to give a uniform gel preparation having a pH of 7.00 and a vis-cosity of 2,000 centipoises.
Examele 20 0.02 g of ~ater-soluble azulene was dissolved in 47.28 g of sterilized water, and to this solution, 11 g of a 4% aqueous solution of carboxyvinyl polymer were added while stirring, and then, 29.7 g of a 2% aqueous solution of triethanolamine were added in small portions while stirring to give a uniform gel hav-ing a pH of 6.90 and a viscosity of 28,000 centipoises.
12 g of an aqueous solution of sodium chloride were added to the above gel in small portions while stirring, to give a uniform gel preparation having a pH of 7.00 and a viscosity of
3,000 centipoises.
Example 21 0.02 g of vitamin B12 was dissolved in 90.98 g of sterilized purified water, and to this solution 7.5 g of a 1%
aqueous solution of carboxyvinyl polymer were added while stir-ring. Subsequently, 1.5 g of a 2% aqueous solution of sodium hydroxide was added to give a uniform gel preparation having a ~0 pH of 7.Q0 and a viscosity of 2,000 centipoises.
Example 22 0.02 g of vitamin B12 was dissolved in 89.28 g of steri-lized purified water, and to this solution 7.5 g of a 4% aqueous solution of carboxyvinyl pol~mer were added while stirring. Sub-sequently, 3.2 g of a 10% aqueous solution of sodium hydroxide were added in small portions w~ile stirring to give a uniform gel preparation having a p~ of 7.00 and a viscosity of 40,000 centi-poises.
Example 23 0.1 g of allantoin was dissolved in 87.3 g of sterilized purified w~ter while stirring, an~ to this solution, 7.5 g of a 1% a~ueous solution of carboxyvinyl polymer were added while stir-. _ ~5834 ring, and subsequently 5.1 g of a 2% aqueous solution of trie-thanolamine were added in small portions while stirring to give a uniform gel preparation having a pH of 7.00 and a viscosity of ~,000 centipoises.
Example 24 O.1 g of allantoin was dissolved in 53. 5 g of sterilized purified water while heating gently. To this solution, 20 g of a 4% aqueous solution of carboxyvinyl polymer were added while stirring and subsequently 26. 4 g of a 2% aqueous solution of tri-ethanolamine were added in small portions while stirring to givea uniform gel preparation having a pH of 6.95 and a viscosity of 40,000 centipoises.
Example 2 5 To 20 g of propylene glycol heated to about 70C on a water bath, 0.05 g of flavin-adenin-dinucleotide was dissolved and the solution was cooled. To this solution, 66.65 g of steri-li-zed purified water and 10 g of a 1% aqueous solution of car-boxyvinyl polymer were added while stirring to give a unifonm solution. 3.3 g of a 2% aqueous solution of monoethanolamine were added in cmall portions to the above solution, to give a uniform gel preparation having a pH of 7.00 and a viscosity of 5,000 centipoises.
Example 26 To 20 g of propylene glycol heated to about 70C on a water bath, 0.1 g of flavin-adenin-dinucleotide was dissolved and the solution was cooledO To this solution, 21.9 g of steri-lized purified water and 25 g of a 4% aqueous solution of carbo-xyvinyl polymer were added while stirring to give a uniform solu-;~ tion. Then, 3.3 g of a 2% aqueous solution of monoethanolamine were added while stirring in small portions to the above solutionto give a uniform gel preparation having a p~ of 6.99 and a vis-cosity of 50,000 centipoises.
Example 27 0.02 g of water-soluble azulene was dissolved in 83.23 g of sterilized purified water. To this solution, 10 g of a 1%
aqueous solution of carboxyvinyl polymer were added while stir-ring and subsequently 6.75 g of a 2% aqueous solution of trie-thanolamine were added in small portions while stirring to give a uniform gel preparation having a pH of 7.00 and a viscosity of
Example 21 0.02 g of vitamin B12 was dissolved in 90.98 g of sterilized purified water, and to this solution 7.5 g of a 1%
aqueous solution of carboxyvinyl polymer were added while stir-ring. Subsequently, 1.5 g of a 2% aqueous solution of sodium hydroxide was added to give a uniform gel preparation having a ~0 pH of 7.Q0 and a viscosity of 2,000 centipoises.
Example 22 0.02 g of vitamin B12 was dissolved in 89.28 g of steri-lized purified water, and to this solution 7.5 g of a 4% aqueous solution of carboxyvinyl pol~mer were added while stirring. Sub-sequently, 3.2 g of a 10% aqueous solution of sodium hydroxide were added in small portions w~ile stirring to give a uniform gel preparation having a p~ of 7.00 and a viscosity of 40,000 centi-poises.
Example 23 0.1 g of allantoin was dissolved in 87.3 g of sterilized purified w~ter while stirring, an~ to this solution, 7.5 g of a 1% a~ueous solution of carboxyvinyl polymer were added while stir-. _ ~5834 ring, and subsequently 5.1 g of a 2% aqueous solution of trie-thanolamine were added in small portions while stirring to give a uniform gel preparation having a pH of 7.00 and a viscosity of ~,000 centipoises.
Example 24 O.1 g of allantoin was dissolved in 53. 5 g of sterilized purified water while heating gently. To this solution, 20 g of a 4% aqueous solution of carboxyvinyl polymer were added while stirring and subsequently 26. 4 g of a 2% aqueous solution of tri-ethanolamine were added in small portions while stirring to givea uniform gel preparation having a pH of 6.95 and a viscosity of 40,000 centipoises.
Example 2 5 To 20 g of propylene glycol heated to about 70C on a water bath, 0.05 g of flavin-adenin-dinucleotide was dissolved and the solution was cooled. To this solution, 66.65 g of steri-li-zed purified water and 10 g of a 1% aqueous solution of car-boxyvinyl polymer were added while stirring to give a unifonm solution. 3.3 g of a 2% aqueous solution of monoethanolamine were added in cmall portions to the above solution, to give a uniform gel preparation having a pH of 7.00 and a viscosity of 5,000 centipoises.
Example 26 To 20 g of propylene glycol heated to about 70C on a water bath, 0.1 g of flavin-adenin-dinucleotide was dissolved and the solution was cooledO To this solution, 21.9 g of steri-lized purified water and 25 g of a 4% aqueous solution of carbo-xyvinyl polymer were added while stirring to give a uniform solu-;~ tion. Then, 3.3 g of a 2% aqueous solution of monoethanolamine were added while stirring in small portions to the above solutionto give a uniform gel preparation having a p~ of 6.99 and a vis-cosity of 50,000 centipoises.
Example 27 0.02 g of water-soluble azulene was dissolved in 83.23 g of sterilized purified water. To this solution, 10 g of a 1%
aqueous solution of carboxyvinyl polymer were added while stir-ring and subsequently 6.75 g of a 2% aqueous solution of trie-thanolamine were added in small portions while stirring to give a uniform gel preparation having a pH of 7.00 and a viscosity of
4,000 centipoises.
Example 28 To 20 g of propylene glycol heated to about 70C on a water bath, 0.05 g of butyric acid ester of riboflavin was dis-solved and the solution was cooled. To this solution, 66.65 g of sterilized purified water and 10 g of a 1% aqueous solution of carboxyvinyl polymer were added while stirring, and then, 3.3 g of a 2% aqueous solution of monoethanolamine were added in small portions while stirring to give a uniform gel preparation having a pH of 8.00 and a viscosity of 5,200 centipoises.
Example 29 0.02 g of vitamin B12 was dissolved in 62.18 g of steri-lized purified water, and to this solution. 11 g of a 4% aqueous solution of carboxyvinyl polymer were added while stirring. Sub-sequently, 8.8 g of a 2% aqueous solution of sodium hydroxide were added in small portions to the above mixture giving a uni-form gel having a pH of 6.90 and a viscosity of 29,000 centi-poises.
To the above gel, 18 g of a 1% aqueous solution of so-dium chloride were added while stirring in small portions to give a uniform gel preparation having a pH of 7.00 and a viscosity of 2,000 centipoises.
Example 30 0.1 g of allantoin was dissolved in 43.2 g of sterilized water while heating gently~ To this solution, 11 g of a 4%
aqueou~ solution of carboxyvinyl polymer were added while stir-ring, and subsequently, 29.7 g of 2~o aqueous solution of tri-ethanolamine were added while stirring to give a uniform gel having a pH of 6.90 and a viscosity of 28,000 centipoises.
To the above gel, 16 g of a 1% aqueous solution of so-dium chloride were added in small portions while stirring to give a uniform gel preparation having a pH of 7.00 and a viscosity of 2,000 centipoises.
Example 31 To 20 g of propylene glycol heated to about 70C on a water bath, 0.05 g of flavin-adenin-dinucleotide was dissolved.
After cooling the solution, 41.95 g of sterilized purified water and 12 g of a 4% aqueous solution of carboxyvinyl polymer were - added while stirring, and then, 16 g of a 2% aqueous solution of monoethanolamine were added in small portions to give a uniform gel having a pH of 6.80 and a viscosity of 34,000 centipoises.
' To the above gel, 10 g of a 1% aqueous ~olution of so-dium chloride were added w~ile stirring to give a uniform gel ; preparation having a pH of 7.00 and a viscosity of 5,000 centi-poises.
Example 32 2 g of boric acid were dissolved in 83.96 g of steri-lized purified water while heating gently on a water bath. After cooling, 12 g of a 4% aqueous solution of carboxyvinyl polymer were added to the above solution while stirring and then, 1.92 g of lOYo aqueous solution of sodium hydroxide was added in small portions w~ile stirring to give a uniform gel.
To the above gel, 0.12 g of sodium chloride was added in small portions and the viscosity of the gel dropped substan-tially. Stirring was continued to give a uniform gel preparationhaving a pH of 7.00 and a viscosity of 3,000 centipoises.
Example_33 To 25 g of propylene glycol heated to about 90C, 0.5 g of prednisolone was dissolved, and then, 61.28 g of sterilized purified water and 11.5 g of a 4% aqueous solution of carboxy-vinyl polymer were added while stirring.
To the above solution, 1.6 g of a 10% aqueous solution of sodium hydroxide was added in small portions while stirring to give a uniform gel. To this gel, 0.12 g of sodium chloride was added in small portions while stirring to give a uniform gel preparation having a pH of 7.00 and a viscosity of 2,200 centi-poises.
Example 34 To a mixture of 86.56 g of sterilized purified water and 11 g of a 4% aqueous solution of carboxyvinyl polymer, 1.76 g of a 10% aqueous solution of sodium hydroxide was added while stirring to give a uniform gel. And then, 0.18 g of sodium chlo-ride was added in small portions while stirring to drop the vis-cosity. Subsequently, 0.5 g of chloramphenicol powder was added to the above gel, and the mixture was thoroughly stirred to give a uniform gel preparation having a pH of 7.00 and a viscosity of 2,000 centipoises.
Example 35 0.02 g of water-soluble azulene was dissolved in 87.1 g of sterilized purified water. To this solution, 11 g of a 4%
aqueous solution of carboxyvinyl polymer were added while stir-ring. Subsequently, 1.76 g of a 10% aqueous solution of sodium hydroxide was added in small portions while stirring to give a uniform gel.
To the above gel, 0.12 g of sodium chloride was added in small portions to drop the viscosity and to give a uniform gel preparation having a pH of 7.00 and a viscosity of 4,000 centi-poises.
Example 36 Allantoin was dissolved in 86.46 g of sterilized puri-fied water, and to this solution, 11 g of a 4% aqueous solution of carboxyvinyl polymer were added while stirring, and 1.76 g of a 10% aqueouQ solution of sodium hydroxide was added in small portions while stirring thoroughly to give a uniform gel. Subse-quently, while stirring the a~ove gel, 0.18 g of sodium chloride was added in small portions to drop the viscosity of the gel and to give a uniform gel preparation having a pH of 7.00 and a visco-sity of 2,000 centipoises.
Example 37 Into 20 g of propylene glycol heated to about 70C 0.05g of flavin-adenin-dinucleotide was dissolved. After cooling, 66.06 g of sterilized purified water and 12 g of a 4% aqueous solution of carbo~yvinyl polymer were added to the above solution, and 1.8 g of a 10% aqueous solution of sodium hydroxide was added in small portions while stirring to give a uniform gel. Then, 0.09 g of sodium chloride was added in small portions while stir-ring to give a uniform gel preparation having a pH of 7.00 and a viscosity of 5,000 centipoises.
Example 38 Into 25 g of propylene glycol heated to about 90C 0.05 g of fluocinonide was dissolved. To this solution, 60.55 g of sterilized purified water and 12 g of a 1% aqueous solution of carboxyvinyl polymer were added while stirring thoroughly. And ; then, 2.4 g of a 2% aqueous solution of sodium hydroxide were added to the above solution while stirring giving a gel prepara-tion having a pH of 6.70 and a viscosity of 3,400 centipoises.
Example 39 Into 25 g of propylene glycol heated to about 90C 0.05 g of fluocinonide was dissolved. ~o this solution, 43.45 g of sterilized purified water and 11.5 g of a 4% aqueous solution of car~oxyvinyl polymer were added while stirring. To this solution, li~5834 8 g of a ~O aqueous solution of sodium hydroxide were added while stirring to give a uniform gel having a pH of 6.92 and a visco-sity of 33,000 centipoises.
Subsequently, 12 g of a 1% aqueous solution of sodium chloride were added in small portions to the above gel while stir-ring to give a uniform gel preparation having a pH of 6.96 and a viscosity of 2,200 centipoises.
Example 40 Into 25 g of propylene glycol heated to about 90C 0.05 g of fluocinonide was dissolved. To this solution, 45.95 g of sterilized purified water and 25 g of 4% aqueous solution of car-boxyvinyl polymer were added while stirring thoroughly. Then, 4 g of a 10% aqueous solution of sodium hydroxide were added to the above solution while stirring thoroughly to give a gel pre-paration having a pH of 6.75 and a viscosity of 41,000 centipoises.
, .
Example 28 To 20 g of propylene glycol heated to about 70C on a water bath, 0.05 g of butyric acid ester of riboflavin was dis-solved and the solution was cooled. To this solution, 66.65 g of sterilized purified water and 10 g of a 1% aqueous solution of carboxyvinyl polymer were added while stirring, and then, 3.3 g of a 2% aqueous solution of monoethanolamine were added in small portions while stirring to give a uniform gel preparation having a pH of 8.00 and a viscosity of 5,200 centipoises.
Example 29 0.02 g of vitamin B12 was dissolved in 62.18 g of steri-lized purified water, and to this solution. 11 g of a 4% aqueous solution of carboxyvinyl polymer were added while stirring. Sub-sequently, 8.8 g of a 2% aqueous solution of sodium hydroxide were added in small portions to the above mixture giving a uni-form gel having a pH of 6.90 and a viscosity of 29,000 centi-poises.
To the above gel, 18 g of a 1% aqueous solution of so-dium chloride were added while stirring in small portions to give a uniform gel preparation having a pH of 7.00 and a viscosity of 2,000 centipoises.
Example 30 0.1 g of allantoin was dissolved in 43.2 g of sterilized water while heating gently~ To this solution, 11 g of a 4%
aqueou~ solution of carboxyvinyl polymer were added while stir-ring, and subsequently, 29.7 g of 2~o aqueous solution of tri-ethanolamine were added while stirring to give a uniform gel having a pH of 6.90 and a viscosity of 28,000 centipoises.
To the above gel, 16 g of a 1% aqueous solution of so-dium chloride were added in small portions while stirring to give a uniform gel preparation having a pH of 7.00 and a viscosity of 2,000 centipoises.
Example 31 To 20 g of propylene glycol heated to about 70C on a water bath, 0.05 g of flavin-adenin-dinucleotide was dissolved.
After cooling the solution, 41.95 g of sterilized purified water and 12 g of a 4% aqueous solution of carboxyvinyl polymer were - added while stirring, and then, 16 g of a 2% aqueous solution of monoethanolamine were added in small portions to give a uniform gel having a pH of 6.80 and a viscosity of 34,000 centipoises.
' To the above gel, 10 g of a 1% aqueous ~olution of so-dium chloride were added w~ile stirring to give a uniform gel ; preparation having a pH of 7.00 and a viscosity of 5,000 centi-poises.
Example 32 2 g of boric acid were dissolved in 83.96 g of steri-lized purified water while heating gently on a water bath. After cooling, 12 g of a 4% aqueous solution of carboxyvinyl polymer were added to the above solution while stirring and then, 1.92 g of lOYo aqueous solution of sodium hydroxide was added in small portions w~ile stirring to give a uniform gel.
To the above gel, 0.12 g of sodium chloride was added in small portions and the viscosity of the gel dropped substan-tially. Stirring was continued to give a uniform gel preparationhaving a pH of 7.00 and a viscosity of 3,000 centipoises.
Example_33 To 25 g of propylene glycol heated to about 90C, 0.5 g of prednisolone was dissolved, and then, 61.28 g of sterilized purified water and 11.5 g of a 4% aqueous solution of carboxy-vinyl polymer were added while stirring.
To the above solution, 1.6 g of a 10% aqueous solution of sodium hydroxide was added in small portions while stirring to give a uniform gel. To this gel, 0.12 g of sodium chloride was added in small portions while stirring to give a uniform gel preparation having a pH of 7.00 and a viscosity of 2,200 centi-poises.
Example 34 To a mixture of 86.56 g of sterilized purified water and 11 g of a 4% aqueous solution of carboxyvinyl polymer, 1.76 g of a 10% aqueous solution of sodium hydroxide was added while stirring to give a uniform gel. And then, 0.18 g of sodium chlo-ride was added in small portions while stirring to drop the vis-cosity. Subsequently, 0.5 g of chloramphenicol powder was added to the above gel, and the mixture was thoroughly stirred to give a uniform gel preparation having a pH of 7.00 and a viscosity of 2,000 centipoises.
Example 35 0.02 g of water-soluble azulene was dissolved in 87.1 g of sterilized purified water. To this solution, 11 g of a 4%
aqueous solution of carboxyvinyl polymer were added while stir-ring. Subsequently, 1.76 g of a 10% aqueous solution of sodium hydroxide was added in small portions while stirring to give a uniform gel.
To the above gel, 0.12 g of sodium chloride was added in small portions to drop the viscosity and to give a uniform gel preparation having a pH of 7.00 and a viscosity of 4,000 centi-poises.
Example 36 Allantoin was dissolved in 86.46 g of sterilized puri-fied water, and to this solution, 11 g of a 4% aqueous solution of carboxyvinyl polymer were added while stirring, and 1.76 g of a 10% aqueouQ solution of sodium hydroxide was added in small portions while stirring thoroughly to give a uniform gel. Subse-quently, while stirring the a~ove gel, 0.18 g of sodium chloride was added in small portions to drop the viscosity of the gel and to give a uniform gel preparation having a pH of 7.00 and a visco-sity of 2,000 centipoises.
Example 37 Into 20 g of propylene glycol heated to about 70C 0.05g of flavin-adenin-dinucleotide was dissolved. After cooling, 66.06 g of sterilized purified water and 12 g of a 4% aqueous solution of carbo~yvinyl polymer were added to the above solution, and 1.8 g of a 10% aqueous solution of sodium hydroxide was added in small portions while stirring to give a uniform gel. Then, 0.09 g of sodium chloride was added in small portions while stir-ring to give a uniform gel preparation having a pH of 7.00 and a viscosity of 5,000 centipoises.
Example 38 Into 25 g of propylene glycol heated to about 90C 0.05 g of fluocinonide was dissolved. To this solution, 60.55 g of sterilized purified water and 12 g of a 1% aqueous solution of carboxyvinyl polymer were added while stirring thoroughly. And ; then, 2.4 g of a 2% aqueous solution of sodium hydroxide were added to the above solution while stirring giving a gel prepara-tion having a pH of 6.70 and a viscosity of 3,400 centipoises.
Example 39 Into 25 g of propylene glycol heated to about 90C 0.05 g of fluocinonide was dissolved. ~o this solution, 43.45 g of sterilized purified water and 11.5 g of a 4% aqueous solution of car~oxyvinyl polymer were added while stirring. To this solution, li~5834 8 g of a ~O aqueous solution of sodium hydroxide were added while stirring to give a uniform gel having a pH of 6.92 and a visco-sity of 33,000 centipoises.
Subsequently, 12 g of a 1% aqueous solution of sodium chloride were added in small portions to the above gel while stir-ring to give a uniform gel preparation having a pH of 6.96 and a viscosity of 2,200 centipoises.
Example 40 Into 25 g of propylene glycol heated to about 90C 0.05 g of fluocinonide was dissolved. To this solution, 45.95 g of sterilized purified water and 25 g of 4% aqueous solution of car-boxyvinyl polymer were added while stirring thoroughly. Then, 4 g of a 10% aqueous solution of sodium hydroxide were added to the above solution while stirring thoroughly to give a gel pre-paration having a pH of 6.75 and a viscosity of 41,000 centipoises.
, .
Claims (11)
1. An ophthalmic preparation in the form of a gel suitable for application to the eye, which comprises a homo-geneous mixture of an aqueous solution of a carboxyvinyl polymer, having a polymer concentration of 0.05 - 5.0%/0 by weight, a water-soluble basic substance, sodium chloride, and a therapeutically effective amount of an ophthalmic drug, said gel having a pH of 5 to 8 and a viscosity of 1,000 centipoises to 100,000 centipoises at 20°C.
2. A gel according to claim 1, wherein said water-soluble basic substance is selected from the group consisting of alkylamines, dialkylamines, trialkylamines, alkanol-amines, dialkanolamines, trialkanolamines, trimethylol-aminomethanes, ammonia and alkali metal hydroxides.
3. A gel according to claim 1 or 2, wherein said viscosity is above about 2000 centipoises at 20°C.
4. A gel according to claim 1 or 2, wherein said viscosity is about 10,000 to about 100,000 centipoises at 20°C.
5. A gel according to claim 1 or 2, prepared by (a) dissolving or dispersing the ophthalmic drug in an aqueous solution of 0.5 to 5.0% by weight of the carboxyvinyl polymer, and (b) uniformly admixing therewith the water-soluble basic substance and sodium chloride in a sufficient amount to yield said gel having said pH of 5 to 8 and said viscosity of 1,000 centipoises to 100,000 centipoises at 20°C.
6. A process for preparing an ophthalmic preparation in the form of a gel suitable for application to the eye, which prepartion comprises a homogeneous mixture of an aqueous solution of a carboxyvinyl polymer containing 0.05 to 5% by weight of said polymer, a water soluble basic substance, a therapeutically effective amount of an ophthalmic drug, and sodium chloride, the gel having a pH of 5 to 8 and a viscosity of 1,000 to 100,000 centi-poises at 20°C., comprising a) dissolving or dispersing said ophthalmic drug in said aqueous solution of said polymer, neutralizing said carboxyvinyl polymer with said basic substance to a pH of 5 to 8 and introducing said sodium chloride into the mixture, or b) neutralizing said aqueous carboxyvinyl polymer solution containing 0.05 to 5%, by weight, of said polymer with said basic substance to a pH of 5 to 8, and introducing said ophthalmic drug and said sodium chloride into the mixture or c) admixing said ophthalmic drug, aqueous carboxy-vinyl polymer and basic substance to form a mixture having a pH of 5 to 8 and introducing the sodium chloride to said mixture.
7, A process according to claim 6a), wherein said ophthalmic drug is dissolved in water or a water-miscible organic solvent prior to being added to said aqueous solution.
8. A process according to claim 6b), wherein said ophthalmic drug is introduced into the mixture prior to the sodium chloride.
9. A process according to claim 6b), wherein the sodium chloride is introduced into the mixture prior to the ophthalmic drug.
10. A process according to claim 6, wherein said basic substance is selected from the group consisting of alkylamines, dialkylamines, trialkylamines, alkanolamines, dialkanolamines, trialkanolamines, trimethylolaminomethanes, ammonia and alkali metal hydroxides.
11. A process according to claim 6 or 10, wherein said viscosity is above about 2000 centipoises at 20°C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP133216/1977 | 1977-11-07 | ||
| JP52133216A JPS6056684B2 (en) | 1977-11-07 | 1977-11-07 | eye drops |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1105834A true CA1105834A (en) | 1981-07-28 |
Family
ID=15099432
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA312,430A Expired CA1105834A (en) | 1977-11-07 | 1978-09-29 | Ophthalmic preparations and process for producing the same |
Country Status (7)
| Country | Link |
|---|---|
| JP (1) | JPS6056684B2 (en) |
| CA (1) | CA1105834A (en) |
| CH (1) | CH640736A5 (en) |
| DE (1) | DE2839752C2 (en) |
| FR (1) | FR2407714A1 (en) |
| GB (1) | GB2007091B (en) |
| IT (1) | IT1098440B (en) |
Families Citing this family (50)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2013084B (en) * | 1978-01-25 | 1982-07-28 | Alcon Lab Inc | Ophthalmic drug dosage |
| ATE6466T1 (en) | 1979-10-26 | 1984-03-15 | Smith And Nephew Associated Companies P.L.C. | AUTOCLAVABLE EMULSIONS. |
| JPS59122422A (en) * | 1982-12-29 | 1984-07-14 | Toko Yakuhin Kogyo Kk | Anti-inflammatory analgesic gel for oral cavity |
| US6255299B1 (en) | 1985-01-07 | 2001-07-03 | Leo Pharmaceutical Products Ltd. | Opthalmic gel composition and method of treating eye infections |
| GB8500310D0 (en) * | 1985-01-07 | 1985-02-13 | Leo Pharm Prod Ltd | Pharmaceutical preparation |
| US5209927A (en) * | 1985-01-23 | 1993-05-11 | Alcon Laboratories, Inc. | Ophthalmic solution |
| JPS63174924A (en) * | 1987-01-14 | 1988-07-19 | Toko Yakuhin Kogyo Kk | Ointment base and ointment |
| IE63392B1 (en) * | 1988-02-08 | 1995-04-19 | Insite Vision Inc | Ophthalmic suspensions |
| US5188826A (en) * | 1988-02-08 | 1993-02-23 | Insite Vision Incorporated | Topical ophthalmic suspensions |
| US5192535A (en) * | 1988-02-08 | 1993-03-09 | Insite Vision Incorporated | Ophthalmic suspensions |
| US5075104A (en) * | 1989-03-31 | 1991-12-24 | Alcon Laboratories, Inc. | Ophthalmic carboxy vinyl polymer gel for dry eye syndrome |
| US5521222A (en) * | 1989-09-28 | 1996-05-28 | Alcon Laboratories, Inc. | Topical ophthalmic pharmaceutical vehicles |
| US5461081A (en) * | 1989-09-28 | 1995-10-24 | Alcon Laboratories, Inc. | Topical ophthalmic pharmaceutical vehicles |
| US5124154A (en) * | 1990-06-12 | 1992-06-23 | Insite Vision Incorporated | Aminosteroids for ophthalmic use |
| FR2678832B1 (en) * | 1991-07-10 | 1995-03-17 | Europhta Sa Laboratoire | NOVEL OPHTHALMIC COMPOSITIONS WITH IMPROVED RESORPTION AND METHODS OF PREPARING THE SAME. |
| FR2679135B1 (en) * | 1991-07-18 | 1995-05-19 | Europhta Sa Laboratoire | NOVEL OPHTHALMIC COMPOSITIONS WITH IMPROVED ADHESIVITY AND METHODS OF PREPARING THE SAME. |
| JP2873530B2 (en) * | 1991-12-13 | 1999-03-24 | 参天製薬株式会社 | Carboxyvinyl polymer-containing ophthalmic base showing Newtonian viscosity |
| US5340572A (en) * | 1993-02-08 | 1994-08-23 | Insite Vision Incorporated | Alkaline ophthalmic suspensions |
| DE4303818C1 (en) * | 1993-02-10 | 1994-03-31 | Mann Gerhard Chem Pharm Fab | Sterile medicament for topical admin. of dexpanthenol - contg. a polyacrylate carrier to improve stability of active agent |
| EP0711147A1 (en) * | 1993-07-28 | 1996-05-15 | Insite Vision Incorporated | Suspensions for delivery of medicament |
| DE4404990C1 (en) * | 1994-02-17 | 1995-05-04 | Mann Gerhard Chem Pharm Fab | Process for producing a sterile prednisolone gel |
| JPH10500148A (en) | 1994-03-04 | 1998-01-06 | ユニバーシティ オブ ワシントン | Block and graft copolymers and related methods |
| FI951190A (en) * | 1994-03-15 | 1995-09-16 | Senju Pharma Co | A method for stabilizing pranoprofen and a stable liquid preparation of pranoprofen |
| SE9401109D0 (en) * | 1994-03-31 | 1994-03-31 | Leiras Oy | Opthalmic composition II |
| SE9401108D0 (en) * | 1994-03-31 | 1994-03-31 | Leiras Oy | Ophthalmic composition I |
| US6309630B1 (en) * | 1994-05-24 | 2001-10-30 | Insite Vision Incorporated | Non-steroidal anti-inflammatory ophthalmic suspensions |
| CZ285636B6 (en) * | 1995-02-07 | 1999-10-13 | Ústav Makromolekulární Chemie Av Čr | Pharmaceutical preparation applicable in ophthalmology exhibiting prolonged activity and process for preparing thereof |
| US5814655A (en) * | 1996-11-14 | 1998-09-29 | Insite Vision Incorporated | Non-steroidal ophthalmic mixtures |
| US6265444B1 (en) | 1997-05-23 | 2001-07-24 | Insite Vision Incorporated | Ophthalmic composition |
| DE19744113A1 (en) * | 1997-10-06 | 1999-04-15 | Mann Gerhard Chem Pharm Fab | Ophthalmological dexamethasone preparation |
| US6159458A (en) * | 1997-11-04 | 2000-12-12 | Insite Vision | Sustained release ophthalmic compositions containing water soluble medicaments |
| MY116782A (en) | 1997-12-22 | 2004-03-31 | Otsuka Pharma Co Ltd | Water-soluble eye drop |
| WO2000018316A2 (en) * | 1998-09-25 | 2000-04-06 | Alcon Laboratories, Inc. | Sustained release, and comfortable ophthalmic composition and method for ocular therapy |
| IN185228B (en) * | 1999-02-03 | 2000-12-09 | Bakulesh Mafatlal Dr Khamar | |
| CN100467066C (en) | 2001-08-10 | 2009-03-11 | 东丽株式会社 | Polysaccharide-containing compositions and use thereof |
| EP1654002B2 (en) * | 2003-08-07 | 2014-01-29 | Allergan, Inc. | Compositions for delivery of therapeutics into the eyes |
| EP1755616B1 (en) | 2004-04-08 | 2013-08-14 | Advanced Ocular Systems Limited | Treatment of exudative retinopathy with mineralcorticoids |
| US20060093675A1 (en) * | 2004-10-29 | 2006-05-04 | Mathew Ebmeier | Intravaginal treatment of vaginal infections with metronidazole compositions |
| ITRM20050547A1 (en) * | 2005-11-04 | 2007-05-05 | Sooft Italia S R L | OPHTHALMIC GEL COMPOSED OF TRIAMCINOLONE ACETONIDE AND A POLYCRYLIC POLYMER. |
| EP1854477B9 (en) | 2006-03-16 | 2018-03-14 | Dyax Corp. | Peptides inhibiting plasma kallikrein for use in the treatment of ophthalmic disorders. |
| AU2007243334A1 (en) | 2006-04-26 | 2007-11-08 | Aciex Therapeutics, Inc. | Compositions for the treatment and prevention of eyelid swelling |
| CN101939363A (en) | 2008-02-06 | 2011-01-05 | 东丽株式会社 | Aqueous dispersion containing polysaccharide particulate gel and method for producing the same |
| US7842714B2 (en) | 2008-03-03 | 2010-11-30 | Allergan, Inc. | Ketorolac tromethamine compositions for treating ocular pain |
| US9192571B2 (en) | 2008-03-03 | 2015-11-24 | Allergan, Inc. | Ketorolac tromethamine compositions for treating or preventing ocular pain |
| NZ594508A (en) | 2009-02-13 | 2013-12-20 | Fovea Pharmaceuticals | [1, 2, 4] triazolo [1, 5 -a] pyridines as kinase inhibitors |
| JP4777477B2 (en) | 2009-09-30 | 2011-09-21 | ロート製薬株式会社 | Eye drops |
| TW201204723A (en) | 2010-06-22 | 2012-02-01 | Fovea Pharmaceuticals | Heterocyclic compounds, their preparation and their therapeutic application |
| JP5736211B2 (en) * | 2011-03-29 | 2015-06-17 | ロート製薬株式会社 | Ophthalmic composition |
| PT2604298T (en) | 2011-12-15 | 2016-07-12 | Demo Sa Pharmaceutical Ind | Multipurpose solutions for contact lens care comprising chamomile |
| JP6401089B2 (en) * | 2015-03-20 | 2018-10-03 | 三粧化研株式会社 | Spray type skin cleanser |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1012060A (en) * | 1964-10-06 | 1977-06-14 | Gilman N. Cyr | Dimethyl sulfoxide gel preparations |
| DK135267A (en) * | 1971-02-25 | |||
| FR2191941A1 (en) * | 1972-07-10 | 1974-02-08 | Serabonian Giacomo | Gelatinising water-sol and aq liqs - by addn of carboxypolymer and alginic acid salt |
| US3811444A (en) * | 1972-12-27 | 1974-05-21 | Alza Corp | Bioerodible ocular device |
| 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 |
| JPS5842168B2 (en) * | 1974-12-20 | 1983-09-17 | トウコウヤクヒンコウギヨウ カブシキガイシヤ | Method for manufacturing topical preparations |
| 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 |
-
1977
- 1977-11-07 JP JP52133216A patent/JPS6056684B2/en not_active Expired
-
1978
- 1978-08-24 FR FR7824593A patent/FR2407714A1/en active Granted
- 1978-08-25 GB GB7834601A patent/GB2007091B/en not_active Expired
- 1978-09-04 IT IT7827277A patent/IT1098440B/en active
- 1978-09-13 DE DE2839752A patent/DE2839752C2/en not_active Expired
- 1978-09-19 CH CH979478A patent/CH640736A5/en not_active IP Right Cessation
- 1978-09-29 CA CA312,430A patent/CA1105834A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| GB2007091A (en) | 1979-05-16 |
| FR2407714A1 (en) | 1979-06-01 |
| DE2839752A1 (en) | 1979-05-10 |
| IT7827277A0 (en) | 1978-09-04 |
| GB2007091B (en) | 1982-05-19 |
| IT1098440B (en) | 1985-09-07 |
| JPS6056684B2 (en) | 1985-12-11 |
| FR2407714B1 (en) | 1982-09-03 |
| JPS5467021A (en) | 1979-05-30 |
| CH640736A5 (en) | 1984-01-31 |
| DE2839752C2 (en) | 1985-12-12 |
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