WO1998056249A1 - Method for enhancing the activity of glaucoma drugs - Google Patents
Method for enhancing the activity of glaucoma drugs Download PDFInfo
- Publication number
- WO1998056249A1 WO1998056249A1 PCT/US1998/011951 US9811951W WO9856249A1 WO 1998056249 A1 WO1998056249 A1 WO 1998056249A1 US 9811951 W US9811951 W US 9811951W WO 9856249 A1 WO9856249 A1 WO 9856249A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hydrolyzable
- activity
- glaucoma
- enhancing
- compound
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
Definitions
- the present application is directed to the use of a reversible cholinesterase inhibitor to enhance the activity of hydrolyzable glaucoma drugs.
- U.S. Patent No. 4,895,841 is directed to cyclic amine compounds and their pharmaceutical use, in particular, for the treatment of senile dementia.
- the patent discloses the compound, l-benzyl-4-[(5,6-dimethoxy-l-indanon-2yl)methyl]piperidine, also known as
- This application is directed to compositions of E2020 and its isomers and methods for its use in enhancing the activity of hydrolyzable glaucoma drugs.
- the present invention is directed to using l-benzyl-4-[(5,6-dimethoxy-l-indanon- 2yl)methyl]piperidine (E2020) and its stereo and optical isomers, hereinafter "Compound,” to enhance the activity of hydrolyzable glaucoma drugs.
- the Compound is effective in increasing the ocular duration of acetylcholine (exogenous and indigenous), pilocarpine, and other related ophthalmic pharmaceuticals wherein the inhibition of ester hydrolysis by acetylcholinesterase will improve the pharmaceutical's efficacy, especially by increasing its duration of action.
- the Compound is administered, in conjunction with a hydrolyzable glaucoma drug, topically to the eye in a pharmaceutically acceptable vehicle at concentrations of about 0.01 to 1.0 weight percent (wt.%), preferably 0.05 to 0.5 wt.%.
- the Compound can be delivered separately or in the same formulation as the hydrolyzable glaucoma drug.
- Ophthalmic solution formulations may be prepared by dissolving the Compound in a physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the Compound.
- the ophthalmic solution may contain a thickener such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the co ⁇ junctival sac.
- a thickener such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose, methylcellulose, polyvinylpyrrolidone, or the like.
- the active ingredient is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum.
- Sterile ophthalmic gel formulations may be prepared by suspending the active ingredient in a hydrophilic base prepared from the combination of, for example, carbopol-940, or the like, according to the published formulations for analogous ophthalmic preparations; preservatives and tonicity agents can be incorporated.
- a formulation containing the Compound is administered, in conjunction with a hydrolyzable glaucoma drug, to the eye of a person suffering from glaucoma or ocular hypertension 1-4 times per day according to the discretion of a skilled clinician.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Methods and compositions for enhancing the activity of hydrolyzable glaucoma drugs are disclosed.
Description
IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
METHOD FOR ENHANCING THE ACTIVITY OF GLAUCOMA DRUGS
Docket No. 1600PCT EXPRESS MAIL LABEL
No. EL008174957US
The present application is directed to the use of a reversible cholinesterase inhibitor to enhance the activity of hydrolyzable glaucoma drugs.
Background of the Invention
U.S. Patent No. 4,895,841 is directed to cyclic amine compounds and their pharmaceutical use, in particular, for the treatment of senile dementia. The patent discloses the compound, l-benzyl-4-[(5,6-dimethoxy-l-indanon-2yl)methyl]piperidine, also known as
E2020. U.S. Patent No. 5,100,901 and European Patent Application Nos. 0 579 263 Al and 0 296 560 A2 also disclose the compound and are related applications. None of the references disclose the compounds for use in enhancing the activity of hydrolyzable glaucoma drugs.
Summary of the Invention
This application is directed to compositions of E2020 and its isomers and methods for its use in enhancing the activity of hydrolyzable glaucoma drugs.
Description of Preferred Embodiments
The present invention is directed to using l-benzyl-4-[(5,6-dimethoxy-l-indanon- 2yl)methyl]piperidine (E2020) and its stereo and optical isomers, hereinafter "Compound," to enhance the activity of hydrolyzable glaucoma drugs. For example, the Compound is effective in increasing the ocular duration of acetylcholine (exogenous and indigenous), pilocarpine, and other related ophthalmic pharmaceuticals wherein the inhibition of ester
hydrolysis by acetylcholinesterase will improve the pharmaceutical's efficacy, especially by increasing its duration of action.
The Compound is administered, in conjunction with a hydrolyzable glaucoma drug, topically to the eye in a pharmaceutically acceptable vehicle at concentrations of about 0.01 to 1.0 weight percent (wt.%), preferably 0.05 to 0.5 wt.%. The Compound can be delivered separately or in the same formulation as the hydrolyzable glaucoma drug.
Various types of formulations are suitable for topical delivery to the eye. The Compound may be combined with ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution. Ophthalmic solution formulations may be prepared by dissolving the Compound in a physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the Compound. Furthermore, the ophthalmic solution may contain a thickener such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the coηjunctival sac. In order to prepare sterile ophthalmic ointment formulations, the active ingredient is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations may be prepared by suspending the active ingredient in a hydrophilic base prepared from the combination of, for example, carbopol-940, or the like, according to the published formulations for analogous ophthalmic preparations; preservatives and tonicity agents can be incorporated.
A formulation containing the Compound is administered, in conjunction with a hydrolyzable glaucoma drug, to the eye of a person suffering from glaucoma or ocular hypertension 1-4 times per day according to the discretion of a skilled clinician.
The following examples are illustrative, but not limiting.
Example 1
Wt.% Based
Ingredient on Free Base
Compound (free base or 0.1 hydrochloride salt)
Dibasic Sodium Phosphate (Anhydrous) 0.50
Sodium Chloride 0.60
Benzalkonium Chloride Solution (10%) 0.01 + 3% XS
Hydrochloric Acid or Sodium Hydroxide Adj. pH 6.8-7.2
Purified Water Q.S.
Example 2
Wt.% Based
Ingredient on Free Base
Compound (free base or 0.1 hydrochloride salt)
Benzalkonium Chloride 0.01 + 5% XS
Tris (Hydroxymethyl) Aminomethane 0.5
Sodium Chloride 0.68
Hydroxypropyl Methylcellulose 0.25
Sodium Hydroxide or Hydrochloric Acid Adj. pH 7.4
Purified Water Q.S.
Claims
1. A method for enhancing the activity of hydrolyzable glaucoma drugs which comprises administering a pharmaceutically effective amount of l-benzyl-4-[(5,6- dimethoxy-1 -indanon-2yl)methyl]piperidine or an isomer thereof in conjunction with the hydrolyzable glaucoma drug.
2. The method of Claim 1 wherein the hydrolyzable glaucoma drug is selected from the group consisting of acetylcholine and pilocarpine.
3. A composition for lowering intraocular pressure comprising a pharmaceutically effective amount of a hydrolyzable glaucoma drug and l-benzyl-4-[(5,6- dimethoxy-l-indanon-2yl)methyl]piperidine or an isomer thereof.
4. The composition of Claim 3 wherein the hydrolyzable glaucoma drug is selected from the group consisting of acetylcholine and pilocarpine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU80636/98A AU8063698A (en) | 1997-06-11 | 1998-06-09 | Method for enhancing the activity of glaucoma drugs |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US4934797P | 1997-06-11 | 1997-06-11 | |
| US60/049,347 | 1997-06-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1998056249A1 true WO1998056249A1 (en) | 1998-12-17 |
Family
ID=21959327
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1998/011951 WO1998056249A1 (en) | 1997-06-11 | 1998-06-09 | Method for enhancing the activity of glaucoma drugs |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU8063698A (en) |
| WO (1) | WO1998056249A1 (en) |
-
1998
- 1998-06-09 WO PCT/US1998/011951 patent/WO1998056249A1/en active Application Filing
- 1998-06-09 AU AU80636/98A patent/AU8063698A/en not_active Abandoned
Non-Patent Citations (1)
| Title |
|---|
| DATABASE STN HCAPLUS 1 January 1900 (1900-01-01), XP002910408, Database accession no. 124:194072 * |
Also Published As
| Publication number | Publication date |
|---|---|
| AU8063698A (en) | 1998-12-30 |
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