COMBINATION OF AN ANTIALLERGIC AGENT WITH MUSCARINIC ANTAGONIST AND/OR DOPAMINERGIC AGONIST FOR USE IN PREVENTING/STOPPING OF AXIAL MYOPIA IN HUMAN

Abstract

One of the major issues against the use of muscarinic antagonists or dopamine agonist eyedrops for the controlling of eye growth and prevention of myopia is the unacceptable rate of iatrogenic conjunctivitis or dermatitis. This invention relates to the association of those active principles with an antiallergic component. In alternative the ophthalmic use of a molecule that simultaneously has an antimuscarinic and/or dopaminergic action along with an antihistaminic function.

Claims

1-11. (canceled)

12. A method for stopping axial myopia in a subject in need thereof, said method comprising administering topically or locally to the eye a single active pharmaceutical ingredient (API) having an antiparkinson activity wherein the single API is 0.001% to 3.0% Benztropine or a salt thereof.

13. The method according to claim 1 wherein the single API is 0.1% benztropine or a salt thereof.

14. The method according to claim 1 wherein the single API is Benztropine methansulfonate (mesylate).

15. The method according to claim 1 wherein the single API is administered in the form of an ophthalmic formulation selected in the group consisting of: a sterile eye drops with or without gelificant(s); a sterile solution suitable for contact lens impregnation; a sterile solution suitable for transscleral iontophoresis; or a concentrated solution for impregnation of a solid porous device to be placed in the inferior conjunctival fornix for a sustained release.

16. The method according to claim 4 wherein the ophthalmic formulation further comprises buffers, a solubilizer, gelificants and/or preservatives.

17. The method according to claim 5 wherein buffers are Sodium phosphate monobasic and Sodium phosphate dibasic and/or preservative is Benzalkonium chloride.

18. The method according to claim 4 wherein the ophthalmic formulation comprises: 0.1% Benztropine methanesulfonate (mesylate); 0.05 M Sodium phosphate monobasic; 0.05 M Sodium phosphate dibasic; 0.025% to 0.1% Benzalkonium chloride; and purified water as remainder, wherein the percentages are based on the total weight of the composition.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0023] The combination of active principles or the single (antiparkinsonian) principle for use according to the invention are preferably to be administered ocularly, topically or locally to the eye.

[0024] According to the invention the composition formulated for ophthalmic use may further comprise buffers, solubilizers (such as cyclodextrins, ionic or non ionic surfactants, phospholipidic micellae or similar, microsomes or others), gelificants (such as Hyaluronic acid, hidroxymethyl-cellulose, hidroxypropyl-cellulose, carboxymethylcellulose, Xantan gum, tamarind seed polysaccharide, povidone, carbopol and/or others) and preservatives (such as Benzalkonium chloride, benzoxonium chloride, cetylpyridinium, polyquad and/or others).

[0025] According to the invention the above composition can be a collyrium or a solution suitable for imbibition of a contact lens, or (with appropriate buffers) suitable for ocular iontophoresis or for the inclusion in intraocular, fornix or intrapunctal porous solid insert (biodegradable or not) like polylactate or similar polimers. Preferably, according to the invention the formulation can be sterile eyedrops with or without gelificant(s); a sterile solution suitable for contact lens impregnation; a sterile solution suitable for transscleral iontophoresis; a concentrated solution for impregnation of a solid porous device to be placed in the inferior conjunctival fornix for a sustained release.

[0026] According to the invention preferably the antihistaminic/antiallergic principle includes but is not limited to: cromoglicic acid, Ketotifen, pemirolast, bepotastine besilate, aminophylline, astemizole, brompheniramine, carbinoxamine, cetirizine, chlorpheniramine, clemastine, diphenhydramine, doxylamine, ebastine, embramine, fexofenadine, levocetirizine, loratadine, methdilazine, mizolastine, rupatadine, terfenadine, quercetin, rutine, rosmarinic acid, caffeic acid esters, palmitoylethanolamide (PEA), luteolin, Perilla leaf extract, and Lindera obtusiloba water extract.

[0027] According to the invention preferably the anticholinergic principle includes but is not limited to: atropine base or salts thereof, hyoscyamine base or salts thereof, atropine methonitrate; anisotropine methylbromide, cyclopentolate, homatropine, 8-phenylacetyl homatropinium chloride, scopolamine (hyoscine), norscopolamine, metylscopolamine base or salts thereof, butylscopolamine base or salts thereof, ipratropium base or salts thereof, tiotropium base or salts thereof, oxitropium base or salts thereof, flutropium base or salts thereof, oxyphenonium base or salts thereof, cyclotropium base or salts thereof, cimetropium base or salts thereof, trospium base or salts thereof, xenytropium base or salts thereof, aclidinium base or salts thereof, clidinium base or salts thereof, tropicamide, cycrimine, biperiden, tolterodine, racanisodamine, ethopropazine, solifenacin, darifenacin, mebeverine, procyclidine, propantheline base or salts thereof, glycopyrrolate, isopropamide base or salts thereof, mepenzolate, tridihexethyl, hexocyclium methylsulfate, methoctramine, dicyclomine, flavoxate, oxybutynin, himbacine and analogs (see, e.g., WO 2005/118576; and WO 2006/076564), difenidol (Hexahydro-sila-difenidol, p-fluoro hexahydro-sila-difenidol), pirenzepine, telenzepine, nuvenzepine, rispenzepine and extract of the plants included in solanaceae family in particular the ones included in the tribes: Datureae, Hyoscyameae, Mandragoreae, Solandreae, Solaneae.

[0028] According to the invention preferably the dopaminergic principle, being mainly active on D2 receptors or as Dopamine reuptake inhibitor, includes but is not limited to: apomorphine, R(−)n-propylnorapomorphine, lergotrile, cabergoline, bromocryptine, 2-bromo-α-ergocryptine, dihydroergocryptine, pergolide, lisuride, levodopa, 3,4-dibenzoyl dopamine, dipropyldopamine, N-Methyldopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), quinpirole, 7,8-Dihydroxy-5-phenyl-octahydrobenzo[h]isoquinoline, A-86929, dihydrexidine, dinapsoline, rotigotin, dinoxiline, doxanthrine, SKF81297, SKF-82958, SKF-38393, Fenoldopam, 6-Br-APB, A-68930, A-77636, CY-208,243, SKF-89145, SKF-89626, N, N-Propyldihydrexidine, Talipexole, Piribedil, Pramipexole, Quinelorane, Ropinirole, Sumanirole, cocaine, amphetamines, amantadine rimantadine and adapromine, Amineptine, bromantane, methylphenidate, dexmethylphenidate, difemetorex, fencamfamine, levophacetoperane, medifoxamine, mesocarb, nomifensine, pipradrol, prolintane, pyrovalerone,

[0029] According to the invention preferably the dopaminergic principle, being a dopamine antagonists mainly active on D1 receptors, includes but is not limited to: domperidone, metoclopramide, sulpiride, haloperidol, bulbocapnine, spiroperidol, thioproperazine, fluphenazine, pimozide, spiperone, SCH-23,390, SKF-83,959, Ecopipam (SCH-39,166), Eticlopride, Fallypride, Desmethoxyfallypride, L-741,626 (3-[4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl]methyl-1H-indole), Raclopride, Hydroxyzine, Itopride, SV 293, drugs classified as typical or atypical antipsychotics and Yohimbine.

[0030] According to the invention preferably the principle having a combined activity as anticholinergic and antihistaminic, or as anticholinergic, antihistaminic and dopaminergic (also as DA reuptake inhibitor) can be selected among Antiparkinsonian agents and tricyclic antidepressants thus includes but is not limited to: Benztropine base or salts thereof as Benztropine methanesulfonate (mesylate), etybenzatropine, Trihexyphenidyl, Ditran (JB-329) (70% 1-ethyl-2-pyrrolidinylmethyl-alpha-phenylcyclopentylglycolate and 30% 1-ethyl-3-piperidyl-alpha-phenylcyclopentylglycolate), 1-ethyl-3-piperidyl-alpha-phenylcyclopentylglycolate, methantheline, diphenylpyraline, ketamine, pethidine, tripelennamine, Dimenhydrinate, imipramine and metabolites thereof, amitriptyline and metabolites thereof, nortriptyline, 10-hydroxynortriptyline and desipramine.

[0031] A preferred combination for use according to the invention comprises atropine and Perilla leaf extract or, atropine and Ketotifen fumarate.

[0032] A preferred antiparkinsonian principle for use according to the invention is Benztropine mesylate.

[0033] Preferred buffers are Sodium phosphate monobasic and Sodium phosphate dibasic. Preferred preservative is Benzalkonium chloride.

[0034] A preferred ophthalmic formulation according to the invention comprises:

TABLE-US-00001 atropine sulphate 0.01%-1.0%, Perilla leaf extract 0.01%-5%,   Sodium phosphate monobasic 0.05M, Sodium phosphate dibasic 0.05M, Benzalkonium chloride 0.025%-0.1%,  purified water as remainder

[0035] wherein the percentages are based on the total weight of the composition.

[0036] Another preferred ophthalmic formulation according to the invention comprises:

TABLE-US-00002 atropine sulphate 0.01%-1.0%, Ketotifen fumarate 0.01%-0.1%  Sodium phosphate monobasic 0.05M, Sodium phosphate dibasic 0.05M, Benzalkonium chloride 0.025%-0.1%,  purified water as remainder

[0037] wherein the percentages are based on the total weight of the composition.

[0038] Another preferred ophthalmic formulation according to the invention comprises:

TABLE-US-00003 benztropine mesylate 0.001%-3.0%  Sodium phosphate monobasic 0.05M, Sodium phosphate dibasic 0.05M, Benzalkonium chloride 0.025%-0.1%, purified water as remainder

[0039] wherein the percentages are based on the total weight of the composition.