EP0660703A1 - Topical carbonic anhydrase inhibitor composition - Google Patents
Topical carbonic anhydrase inhibitor compositionInfo
- Publication number
- EP0660703A1 EP0660703A1 EP93906043A EP93906043A EP0660703A1 EP 0660703 A1 EP0660703 A1 EP 0660703A1 EP 93906043 A EP93906043 A EP 93906043A EP 93906043 A EP93906043 A EP 93906043A EP 0660703 A1 EP0660703 A1 EP 0660703A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- carbonic anhydrase
- anhydrase inhibitor
- composition
- sulfonamide
- thieno
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the polycyclic heteroaromatic group can be, for example, two fused five membered aromatic rings with one or more heteroatoms such as 0, S, N; examples include: thienothiophenes, thienofurans, thienopyrroles, furanothiophenes, imidazolthiazoles and, thienothiazoles.
- the polycylic heteroaromatic group can also be a five- embered heteroaromatic ring fused to a six-membered carbocyclic or heterocyclic ring which may or may not be aromatic. Examples include: benzothiophene, thienothiazines, thienothiopyrans or furanothiopyrans.
- composition includes the compound R-(+)-4- ethylamino-3,4-dihydro-2-(3-methoxy)propyl-2H-thieno[3,2-e]- 1,2-thiazine-6-sulfonamide 1,1-dioxide.
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Ophthalmology & Optometry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Compositions and methods for controlling intraocular pressure with carbonic anhydrase inhibitors are disclosed.
Description
TOPICAL CARBONIC ANHYDRASE INHIBITOR COMPOSITION
Summary Of The Invention
This invention is directed to compositions of carbonic anhydrase inhibitors and methods of using the compositions to control intraocular pressure by delivering the compositions topically to the eye.
Background of the Invention
In the past it was believed that sulfonamide carbonic anhydrase inhibitors (CAIs) could not be administered topically to the eye to lower intraocular pressure (IOP). This position was based on the failure of CAIs, which were developed for systemic administration, such as ethoxzolamide and acetazolamide. Failures occurred despite numerous creative formulation attempts. In ensuing years a greater understanding of the properties of ocular tissues and fluids and the overall delivery/penetration process led to the hypothesis that CAIs were ineffective topically because they did not penetrate the cornea well. Four key publications outline this belief: Maren et al., Exp. Eye Res., 36, 457-
480, 1983; Maren in U.S. Patent Nos. 4,619,939 and 4,746,745; and Stein et al. in Amer. J. Ophthal., 95, 222-228, 1983. In these publications the usefulness of selected, topically dosed thiadiazole CAIs with certain water and lipid solubility characteristics (among other things) is disclosed.
The prior art has been driven by the premise that CAIs, to be useful topically, had to be relatively water soluble, see, Ponticello et al., J. Med. Chem., 30, 591-597 (1987); Baldwin et al., J. Med. Chem. 32, 2510-2513 (1989); Prugh et al., J. Med. Chem., 34, 1805-1818 (1991); and Lippa, The Carbonic Anh drases, (Dodgson, Tashian, Gros, Carter eds. )
Plenum Press, New York, New York, 171-181 (1991). The basic strategy for achieving water solubility has been to formulate CAIs at a pH where they are predominantly ionized. It is also clear from the literature that CAIs with low aqueous solubility are not suitable as topically active CAIs. CAIs which are predominantly neutral at physiological pH are not expected to have topical utility when formulated at close to physiological pH. This is perhaps best evidenced by a series of publications which show that formulations of solutions of CAIs at or near physiological pH (i.e., when the drug is predominantly un-ionized) are inferior to formulations at a significantly higher or lower pH (i.e., when the drug is predominantly ionized) both in terms of efficacy and bioavailability: Brechue and Maren Invest. Ophthalmol. Vis. Sci. 1992; 33 (suppl): 2119); Brechue and Maren Invest.
Ophthalmol. Vis. Sc. 1990; 31 (suppl): 741); Conroy and Maren Invest. Ophthalmol. Vis. Sci. 1992; 33 (suppl): 2122).
Applicants have surprisingly found that there are CAIs which fall outside the criteria taught by the prior art which, when administered topically to the eye, will lower IOP.
Brief Summary of the Invention
The CAIs of the present invention possess exceptionally low aqueous solubilities and are effective in lowering and controlling IOP when dosed topically to the eye. They are stable in suspension and are not injurious to the eye. These compounds have aqueous solubilities greater than 10 μg/mL but less than 1000 μg/mL at pH 7.4. CAIs of this invention have octanol/water distribution coefficients (DC) measured at pH 7.4 of from 1.0 to 150. The dissociation constants (K.) of the CAIs of this invention are 1.0 nM or lower.
Detailed Description of the Invention
We have been quite concerned about the side-effects, such as discomfort to the eye, resulting from the use of formulations of CAIs at pHs where they are predominantly ionized. During our search for compounds which lower IOP and are generally well-tolerated we discovered, quite unexpectedly, that CAIs with exceptionally low aqueous solubilities are topically active. Moreover, compounds of this type are topically active when formulated, for example, as suspensions, at pHs where they are generally in un-ionized form. Compositions at these pHs are generally well-tolerated when topically administered to the eye. The CAIs are useful in lowering and controlling (hereinafter "controlling") intraocular pressure associated with conditions such as ocular hypertension and/or glaucoma.
CAIs of this invention have an aqueous solubility greater than 10 μg/mL but less than 1000 μg/mL at pH 7.4. This aqueous solubility is measured, for example, by dissolving or suspending the sulfonamide (in its neutral or salt form) in 0.1 M phosphate buffer with the pH adjusted to 7.4. The mixture is then stirred for at least 16 hours and the pH of the solution is determined and readjusted to pH 7.4 if necessary. In the case where the mixture is a solution, a small amount of a seed crystal of the neutral CAI is added and the mixture is stirred for at least 16 additional hours. This is to initiate crystallization of a potentially supersaturated solution to help insure that the mixture has reached equilibrium. The solid/liquid mixture is filtered through a 0.45 μm filter and the filtrate is assayed in triplicate by HPLC against standards. The solubility as measured includes both the neutral and ionized forms of the CAI. At pH 7.4 the CAIs contemplated by this invention are predominantly un¬ ionized, but there may be up to 10 to 20% of the anionic sulfonamide present (depending on the pKa of the primary
sulfonamide group) . Additionally, for those CAIs with a relatively low pKa amine substituent there can be up to about 10% of cationic and/or zwitterionic fraction.
A measure of the activity of CAIs against Human Carbonic Anhydrase II (HCAII) is their dissociation constant ( -). This parameter is determined using the fluorescence competition assay which uses the fluorescent HCAII:dansylamide complex (dansylamide assay) and is well known in the art, Chen et al., J. Biol. Chem., 242, 5813 (1967) and Ponticello et al., J. Med. Chem., 30, 591 (1987). The CAIs of this invention have K.s of 1.0 riM or lower. Ethoxzolamide, which has a K. of approximately 0.3 nM, is used as a benchmark to determine the relative K., or the ratio of the K. of a given CAI of this invention, to that of ethoxzolamide. The relative K.s for CAIs of this invention are less than 3.3.
CAIs of the present invention have distribution coefficients at pH 7.4 from 1.0 to 150. Distribution coefficients are determined in octanol and water with 0.1 M phosphate buffer at pH 7.4 using methods well-known in the art. This measurement furnishes the distribution of the drug between the two layers and does not differentiate partitioning of the neutral from the ionized forms.
The CAIs of this invention are also stable in suspension, are not injurious to the eye, and are transported into the eye without being substantially structurally modified.
The degree of reactivity of a carbonic anhydrase inhibitor with glutathione (GSH) is one means of determining the potential of that compound to induce either ocular irritation or hypersensitivity following chronic topical- ocular exposure. Compounds that demonstrate significant reactivity in this assay are considered to have a high potential for being injurious to the eye following chronic
topical-ocular exposure and as such do not fall within the scope of this invention. Compounds which show no or only slight reactivity are preferred and compounds which show essentially no reactivity are most preferred. This phenomenon is known in the art and methods useful for assessing the relative reactivity of a CAI are taught in the following references: Conroy et al., Drug Metabolism and Disposition, 12, 614-618 (1984); and Woltersdorf et al., J. Med. Chem., 32, 2486-2492, 1989 and references cited therein.
This invention is not intended to be restricted to a single class of CAIs but includes all CAIs which fall within the parameters set forth herein.
One skilled in the art would be well-informed as to the numerous types of aromatic and heteroaromatic sulfonamides which are effective in inhibiting carbonic anhydrase. In general, these compounds can be defined according to Formula I:
J-S02NH2 Formula 1
wherein the aqueous solubility, DC, and K. are as previously defined and J is a substituted phenyl ring or a mono or polycyclic substituted heteroaromatic group. The monocyclic heteroaromatic group can be, for example, thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, oxazole, or pyridine. The polycyclic heteroaromatic group can be, for example, two fused five membered aromatic rings with one or more heteroatoms such as 0, S, N; examples include: thienothiophenes, thienofurans, thienopyrroles, furanothiophenes, imidazolthiazoles and, thienothiazoles. The polycylic heteroaromatic group can also be a five- embered heteroaromatic ring fused to a six-membered carbocyclic or heterocyclic ring which may or may not be aromatic. Examples
include: benzothiophene, thienothiazines, thienothiopyrans or furanothiopyrans.
The preferred compounds of this invention are depicted by Formula II:
Formula II
wherein the aqueous solubility, DC, and K1 are as previously defined and R and R.. represent substituents attached to either the 4 or 5 position and may be joined together to form a ring and R or R1 can be H.
The most preferred compounds are of Formula III:
Formula III
wherein the aqueous solubility, DC, and K. are as previously defined and Y is either nitrogen or carbon; Rj is one or more substituents selected from H, a substituted or unsubstituted alkyl, alkoxy, aminoalkyl, phenyl, or heteroaromatic group attached to either or both of the ring carbon atoms when Y is nitrogen, or to any one or more of the three ring carbon atoms when Y is carbon; and R4 is a substituted or unsubstituted alkyl, alkenyl, phenyl and/or heteroaromatic group.
CAIs of this invention may possess one or more chiral centers and it is possible that one enantiomer/diasteriomer is
more active than the other. In those cases wherein one enantiomer or diasteriomer is desired, the properties of that enantiomer/diasteriomer are used to determine whether the compound falls within the parameters of the invention.
Many of the CAIs which meet the parameters of the present invention are known in the art and can be prepared by methods known to one skilled in the art, see for example, Hartman et al., J. Med. Chem 35, 3027 (1992) and references cited therein; Barnish et al., J. Med Chem 23, 117 (1980); and commonly assigned U.S. Patent No. 5,153,192 and U.S. Serial
The CAIs are formulated at 0.1-5% for topical delivery to the eye, 1-2 drops, 1-4 times daily according to the discretion of a skilled clinician.
The preferred compositions of the present invention include one or more of the following compounds: R-(+)-3,4- dihydro-2-(4-methoxy)butyl-4-propylamino-2H-thieno-[3,2-e]- l,2-thiazine-6-sulfonamide 1,1-dioxide (Compound 3, Example 1) ; R-(+)-4-ethylamino-3,4-dihydro-2-(4-methoxy)butyl-2H- thieno-[3,2-e]-l,2-thiazine-6-sulfonamide 1,1-dioxide (Compound 2, Example 1); (-)-trans-5,6-dihydro-6-(3- methoxy)propyl-4-propylamino-4H-thieno[2,3-b]thiopyran-2- sulfonamide 7,7-dioxide (Compound 4, Example 2). The most preferred composition includes the compound R-(+)-4- ethylamino-3,4-dihydro-2-(3-methoxy)propyl-2H-thieno[3,2-e]- 1,2-thiazine-6-sulfonamide 1,1-dioxide.
The following examples are illustrative of the CAIs which can be used in the compositions and methods of the present invention. They are in no way limiting.
EXAMPLE 1
The properties of the compounds listed below were obtained using the methods described in this disclosure. These compounds are effective in lowering IOP when delivered topically to the eyes of both rabbits and monkeys.
Aqueous
Compound Solubility
(uσ/mL DH 7.4)
1 484 2 68 3 28
The compounds listed below possess the properties described in the disclosure. These compounds are effective in lowering IOP when delivered topically to the eye of rabbits and/or monkeys.
OPHTHALMIC SUSPENSION
INGREDIENT CONCENTRATION
(wt/v%) R- ( + ) -4-Ethylamino-3 , 4-dihydro-
2-(3-methoxy)propyl-2H-thieno[3,2-e]-
1,2-thiazine-6-sulfonamide 1,1-dioxide
(Compound) 2% + 2% xs
Hydroxypropylmethylcellulose 3% Dibasic Sodium Phosphate 0.2%
Sodium Chloride 0.7%
Disodium Edetate 0.01%
Polysorbate 80 0.05%
Benzalkonium chloride 0.01% NaOH/HCl pH adjust
Purified Water q.s. 100%
The vehicle was prepared by heating 400 mL of purified water to boiling. HPMC (30.0 g) was added and the mixture was stirred vigorously until homogeneous. A separate beaker containing sodium chloride (7.0 g) , dibasic sodium phosphate (2.0 g) , disodium edta (0.1 g) , polysorbate 80 (0.5 g) and benzalkonium chloride (10.5 mL of a 1% solution) was added to
the solution of HPMC and purified water was added to a final volume of 900 mL. The mixture was cooled in an ice bath to room temperature with stirring and the pH was adjusted to 7.2 by the addition of HC1 (3.5 mL of a 1 N solution). The mixture was q.s. to the final weight with purified water
(total purified water of 1010 g) and filtered through a 10 micron filter. The formulation was prepared by the addition of the above HPMC vehicle (15.014 g) to the Compound (0.3074 g) and the mixture was ball milled with 3 mm glass beads (5 g) for 45 hours.
EXAMPLE 4
OPHTHALMIC SUSPENSION
INGREDIENT CONCENTRATION (WF% .
R-(+)-3,4-dihydro-2-(4-methoxybutyl)- 2.0% 4-propylamino-2H-thieno[3,2-e]-l,2- thiazine-6-sulfonamide 1,1-dioxide (Compound)
Carbomer 934P
Sodium Chloride Mannitol
Disodium EDTA
Polysorbate 80
Benzalkonium Chloride Solution
Sodium Hydroxide Hydrochloric Acid
Water for Injection
The above ingredients were mixed together using a method similar to the same general procedure described in Example 3 to furnish the ophthalmic suspension.
Claims
1. A method for controlling intraocular pressure, which comprises: topically administering to the eye a composition which comprises a pharmaceutically effective amount of a carbonic anhydrase inhibitor which is not injurious to the eye and having an aqueous solubility greater than 10 μg/mL but less than 1000 μg/mL at pH 7.4, an octanol/water distribution coefficient from 1.0 - 150 at pH 7.4, and a K1 of 1.0 nM or lower.
2. The method of Claim 1 wherein the carbonic anhydrase inhibitor has the formula:
J-S02NH2
and J is a substituted phenyl ring or a mono or polycyclic substituted heteroaromatic group.
3. The method of Claim 1 wherein the carbonic anhydrase inhibitor has the formula:
and R and R1 are substituents attached to either the 4 or 5 position and may be joined together to form a ring and R or R1 can be H.
4. The method of Claim 1 wherein the carbonic anhydrase inhibitor has the formula:
and Y is N or C ;
R. is H, a substituted or unsubstituted alkyl, alkoxy, a inoalkyl, phenyl or heteroaromatic, group attached to either or both of the ring carbon atoms when Y is nitrogen, or to any one or more of the three ring carbon atoms when Y is carbon; and
R4 is a substituted or unsubstituted alkyl, alkenyl, phenyl, or heteroaromatic group.
5. The method of Claim 1 wherein the carbonic anhydrase inhibitor is selected from the group consisting of R-(+)-3,4- dihydro-2-(4-methoxy)butyl-4-propylamino-2H-thieno-[3,2-e]- l,2-thiazine-6-sulfonamide 1,1-dioxide; R-(+)-4-ethylamino- 3,4-dihydro-2-(4-methoxy)butyl-2H-thieno-[3,2-e]-1,2-thiazine- 6-sulfonamide 1,1-dioxide; (-)-trans-5,6-dihydro-6-(3- methoxy)propyl-4-propylamino-4H-thieno[2,3-b]thiopyran-2- sulfonamide 7,7-dioxide.
6. The method of Claim 1 wherein the carbonic anhydrase inhibitor is R-(+)-4-ethylamino-3,4-dihydro-2-(3- methoxy)propyl-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide.
7. The method of Claim 1 wherein the composition is a suspension.
8. A method for controlling intraocular pressure, which comprises: topically administering to the eye a composition, which comprises a pharmaceutically effective amount of a carbonic anhydrase inhibitor which is not injurious to the eye and having an aqueous solubility greater than 10 μg/mL but less than 1000 μg/mL at pH 7.4, an octanol/water distribution coefficient from 1.0 - 150 at pH 7.4, and a K. of 1.0 nM or lower, the carbonic anhydrase inhibitor having a solution concentration of less than 1000 μg/mL in the composition.
9. A composition for controlling intraocular pressure, comprising a pharmaceutically effective amount of a carbonic anhydrase inhibitor which is not injurious to the eye and having an aqueous solubility greater than 10 Ϊg/mL but less than 1000 Ϊg/mL at pH 7.4, an octanol/water distribution coefficient from 1.0 - 150 at pH 7.4, and a Ki of 1.0 nM or lower.
10. The composition of Claim 9 wherein the carbonic anhydrase inhibitor has the formula:
J-S02NH2
and J is a substituted phenyl ring or a mono or polycyclic substituted heteroaromatic group.
11. The composition of Claim 9 wherein the carbonic anhydrase inhibitor has the formula:
and R and R1 are substituents attached to either the 4 or 5 position and may be joined together to form a ring and R or R1 can be H.
12. The composition of Claim 9 wherein the carbonic anhydrase inhibitor has the formula:
and Y is N or C ;
R3 is H, a substituted or unsubstituted alkyl, alkoxy, aminoalkyl, phenyl or heteroaromatic, group attached to either or both of the ring carbon atoms when Y is nitrogen, or to any one or more of the three ring carbon atoms when Y is carbon; and
R4 is a substituted or unsubstituted alkyl, alkenyl, phenyl, or heteroaromatic group.
13. The composition of Claim 9 wherein the carbonic anhydrase inhibitor is selected from the group consisting of R-(+)-3,4- dihydro-2-(4-methoxy) utyl-4-propylamino-2H-thieno-[3,2-e]- l,2-thiazine-6-sulfonamide 1,1-dioxide; R-(+)-4-ethylamino- 3,4-dihydro-2-(4-methoxy)butyl-2H-thieno-[3,2-e]-1,2-thiazine- 6-sulfonamide 1,1-dioxide; (-)-trans-5,6-dihydro-6-(3- methoxy)propyl-4-propylamino-4H-thieno[2,3-b]thiopyran-2- sulfonamide 7,7-dioxide.
14. The composition of Claim 9 wherein the carbonic anhydrase inhibitor is R-(+)-4-ethylamino-3,4-dihydro-2-(3- methoxy)propyl-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide.
15. A composition for controlling intraocular pressure, comprising a pharmaceutically effective amount of a carbonic anhydrase inhibitor which is not injurious to the eye and having an aqueous solubility greater than 10 μg/mL but less than 1000 μg/mL at pH 7.4, an octanol/water distribution coefficient from 1.0 - 150 at pH 7.4, and a K.. of 1.0 nM or lower, the carbonic anhydrase inhibitor having a solution concentration of less than 1000 μg/mL in the composition.
16. A suspension for controlling intraocular pressure, comprising a carbonic anhydrase inhibitor which is not injurious to the eye and having an aqueous solubility greater than 10 μg/mL but less than 1000 μg/mL at pH 7.4, an octanol/water distribution coefficient from 1.0 - 150 at pH 7.4, and a K. of 1.0 nM or lower.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US94650892A | 1992-09-17 | 1992-09-17 | |
US946508 | 1992-09-17 | ||
PCT/US1993/001434 WO1994006411A1 (en) | 1992-09-17 | 1993-02-18 | Topical carbonic anhydrase inhibitor composition |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0660703A1 true EP0660703A1 (en) | 1995-07-05 |
Family
ID=25484578
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP93906043A Withdrawn EP0660703A1 (en) | 1992-09-17 | 1993-02-18 | Topical carbonic anhydrase inhibitor composition |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0660703A1 (en) |
JP (1) | JPH08501303A (en) |
AU (1) | AU3722793A (en) |
CA (1) | CA2141879A1 (en) |
WO (1) | WO1994006411A1 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2754712B1 (en) | 1996-10-17 | 1999-09-03 | Merck Sharp Dohme Chibret Lab | OPHTHALMIC COMPOSITIONS |
EP3096740B1 (en) * | 2014-01-24 | 2020-09-30 | Sentiss Pharma Private Limited | Pharmaceutical composition comprising brinzolamide |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5153192A (en) * | 1990-04-09 | 1992-10-06 | Alcon Laboratories, Inc. | Thiophene sulfonamides useful as carbonic anhydrase inhibitors |
IE911192A1 (en) * | 1990-04-12 | 1991-10-23 | Merck & Co Inc | Substituted aromatic sulfonamides as antiglaucoma agents |
US5157129A (en) * | 1990-04-18 | 1992-10-20 | Merck & Co., Inc. | Enantiospecific synthesis of s-(+)-5,6-dihydro-4-(r-amino)-4h-thieno(2,3-b)thiopyran-2-sulfonamide-7,7-dioxide |
US5091409A (en) * | 1990-05-17 | 1992-02-25 | Merck & Co., Inc. | 4-alkylamino-6-(C3-5 -hydrocarbyl)thieno[2,3-B]thiopyran-2-sulfonamide-7,7-dioxides |
US5093332A (en) * | 1990-10-01 | 1992-03-03 | Merck & Co., Inc. | Substituted thieno(2,3-b)(1,4)thiazine-6-sulfonamides as antiglaucoma agents |
ATE141502T1 (en) * | 1991-01-15 | 1996-09-15 | Alcon Lab Inc | USE OF CARRAGEENAN IN TOPICAL OPHTHALMOLOGICAL COMPOSITIONS |
US5175284A (en) * | 1991-10-15 | 1992-12-29 | Merck & Co., Inc. | Tricyclic thienothiopyrans as pharmaceutical intermediates |
-
1993
- 1993-02-18 CA CA002141879A patent/CA2141879A1/en not_active Abandoned
- 1993-02-18 WO PCT/US1993/001434 patent/WO1994006411A1/en not_active Application Discontinuation
- 1993-02-18 EP EP93906043A patent/EP0660703A1/en not_active Withdrawn
- 1993-02-18 JP JP6508049A patent/JPH08501303A/en active Pending
- 1993-02-18 AU AU37227/93A patent/AU3722793A/en not_active Abandoned
Non-Patent Citations (1)
Title |
---|
See references of WO9406411A1 * |
Also Published As
Publication number | Publication date |
---|---|
JPH08501303A (en) | 1996-02-13 |
WO1994006411A1 (en) | 1994-03-31 |
AU3722793A (en) | 1994-04-12 |
CA2141879A1 (en) | 1994-03-31 |
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