MXPA01000803A - Cholinergic agents in the treatment of presbyopia - Google Patents

Abstract

A method for increasing or decreasing parasympathetic/cholinergic/ciliary tonic contraction in order to restore the resting portion of the eye and allow normal positive and negative accommodation includes administering to a presbyopic subject an effective amount of a muscarinic agent.

Description

COLINERGIC AGENTS IN THE TREATMENT OF PRESERVATION Presbyopia, which occurs after a middle age, is the inability of an eye to focus properly. This ocular pathology related to age manifests itself in a loss of accommodation ability. The ability of accommodation is the ability of the eye, through the lens, to focus near or far objects changing the shape of the lens to become more spherical, or convex.

The ciliary muscle controls the shape of the lens through suspended suspensory ligaments called zonules. Like most smooth muscles, the ciliary muscle has a double innervation, which receives sympathetic and parasympathetic fibers.

In the ciliary muscle, the contraction necessary for accommodation is under parasympathetic or cholinergic control. While this parasympathetic control is predominant, sympathetic, or adrenergic, innervation is opposed to cholinergic control and plays a minor role in allowing ciliary muscle relaxation.

Most theories of accommodation assume that the physiological resting condition of accommodation occurs REF. DO NOT. 126472 when the emetropic eye focuses on a distant objective, in demand of a good resolution. The fact that the optical value for the location of this distant objective can be established as zero diopter of the eye has tended to perpetuate the concept that active accommodation is unidirectional in the direction of a nearby object.

However, if it is considered that if the normal accommodation stimulus is visual by nature, then the resting state of the eye must be determined by the removal of all visual stimuli, such as in complete darkness or in a luminous visual area. but completely empty. This state of rest of the eye has been called "tonic accommodation", "space myopia", "myopia of the sky", and averages of approximately ID in extremely low or total darkness, but can be as high as 2D myopia.

This implies that the resting state of the accommodation is present when the eye is focused for objects at about one meter. Consequently, distant objects will be focused on the retina by a negative active accommodation and nearby objects could be focused by a positive active accommodation.

Consequently, in the state of natural rest of the eye, the parasympathetic / cholinergic system maintains the tone of the ciliary muscle, that is, the ciliary muscle contracts and the zonular tension relaxes in such a way that the lens is more spherical and in a position advanced by increasing the refractive power of the eye. Then, the eye is in a state of "tonic accommodation" and with the appropriate stimulus it is capable of an additional positive active accommodation as well as a negative active accommodation.

BRIEF DESCRIPTION OF THE INVENTION A method according to the present invention provides an increase or decrease in a parasympathetic / cholinergic / ciliary tonic contraction in order to restore the resting position of the eye and allows normal positive and negative accommodation. This action of the ciliary muscle under the parasympathetic innervation provides relaxation of zonules which allows the lens to assume a more spherical shape.

A method according to the present invention comprises administering to a prespecified subject an effective amount of a muscarinic agonist or antagonist.

The agonist / antagonist is administered in a pharmaceutically acceptable ophthalmic formulation, preferably the agonist is typically administered by application of the formulation to the eye in a sterile non-irritating solution or suspension. In this regard, the formulation is preferably at a pH compatible with the eye. More particularly, according to the present invention, a muscarinic agent can be selected to act on several M receptors of the ciliary muscle.

DETAILED DESCRIPTION OF THE INVENTION While the treatment of this invention is not limited to the validity of a proposed mechanism of action, it is believed that the action of the circular fibers of the ciliary muscle causes relaxation of the zonules and allows a greater curvature or sphericity of the lens. The radial / longitudinal fibers of the ciliary muscle relax or stretch which allows the lens to move forward. However, as the lens continues to grow throughout life, its increased size and concomitant loss of elasticity exceeds the capacity of the ciliary muscle to be made. a change of appropriate accommodation. In addition, the resting state of the eye is also expected to change.

Also, studies of brain aging have shown a loss of cholinergic system function that is due to a decline in the neurotransmitter substance acetylcholine. This is probably due to decreased production by the enzyme colineacetyl transferase (CHAT) or acetylcholine synthetase while there is no decline in cholinergic receptor cells with age. That is, the ciliary muscle has the same number of receptors and the contractile capacity of the muscle is the same in young and old individuals.

According to the present invention, the muscarinic receptor subtypes allow the selective contraction or relaxation of the circular or longitudinal fibers of the ciliary muscle by action at the Mi-M5 receptors.

A summary of the receptor subtypes is given in the Table 1.

TABLE 1 Receiver Tissue Function Subtype or Cellular Mechanisms Signage M_ Contraction or secretion Pl, Ca M2 Relaxation cAMP M3 Contraction or secretion PU, Ca M4 Relaxation cAMP M5 Contraction or secretion Pl, Ca Where Pl Hydrolysis phosphoinositide (stimulating response) Ca Increase in free intracellular calcium (stimulating response) CAMP Increase in the formation of cyclic adenosine monophosphate (AMP) (inhibitory response) The M3 receptor subtype is the most common and is seen predominantly in the circular fibers and the M5 receptor is predominant in the longitudinal fibers. Consequently, it is possible that inhibition of the M5 receptor and / or stimulation of the sympathetic nervous system may allow the relaxation / stretching of the longitudinal fibers.

The compounds useful in the practice of the present invention are any muscarinic agonist or antagonist. As used herein, the term "muscarinic antagonist" means any compound that produces a net sympatholytic response in autonomous neuroeffective junctions. The parasympathetic people who block the parasympathetic system are muscarinic antagonists and the parasympathomimetic agents that stimulate the parasympathetic system are muscarinic agonists. Neuroeffective junctions are considered cholinergic if they are energized by muscarinic agonists such as acetylcholine.

Without limiting the present invention to specific groups and listed compounds, the following is a list of representative muscarinic agonists and antagonists useful in the present invention.

Muscarinic agonists In general, muscarinic agonists are M non-selective and are parasympathomimetic and stimulate the system parasympathetic. Such muscarinic agonists include, but are not limited to: Filocarpine Isopilocarpine lactam Carbacol Betanecol Methacholine Muscarine Muscarinic Antagonists Muscarinic antagonists are parasympatholytic and block the parasympathetic system.

These antagonists have a higher affinity for the designated receptors, but also bind to the other receptor subtypes with less affinity. Such muscarinic antagonists include, but are not limited to, in relation to M receptors: My Pirenzepine, Telensepine, (M? / M4) trihexyphenidyl M2 (+) (11- (. {2- [(diethylaminomethyl] -l-piperdidinyl} acetyl) -5,1-di-hydro-6H-pyrido (2,3-b) (1, 4) benzodiazepin-6-one; (+) 5,11 dihydro-ll-. { [2- [(dipropylamino) methyl] -1- piperidinyl) amino] carbonyl} -6H-pyrido (2,3-b) (1,4) benzodiazepin-6-one; Himbacin, triptiramine M3 diphenylacetoxy-N-methylpiperidine metiodide, (+) p-fluoro-hexahydro-sila-diphenidol hydrochloride M4 Pirenzepines, Telenzepine.

Analogs of the above compounds that function as muscarinic agonists specifically intend to be covered by the present invention. The ability of such analogs to restore the resting position of the eye and allow for normal positive and negative accommodation can easily be proved using nothing more than routine experimentation.

The method according to the present invention is particularly suited to subjects other than are free of indications for ophthalmic treatments using muscarinic agonists.

The agonists according to the present invention can be administered as such or in the form of a pharmaceutically acceptable salt. When used in a In the formulation, the muscarinic agonist salts should be acceptable both pharmacologically and pharmaceutically, but the non-pharmaceutically acceptable salts can be conveniently used to prepare the free active compound or its pharmaceutically acceptable salts.

Many of the compounds of the present invention are known in the art for their purposes, and are known to be safe under normal conditions of use. Therefore, the treatment of the present invention can be administered by substantially conventional means, consistent with the treatments for the eyes, and by avoiding irritation, discomfort - from the need for unusual application procedures.

The formulation of the present invention can include any formulation whose compounds of the invention can be delivered to the eye. Preferably, the muscarinic agonists of the present invention are applied to the eye in a typical preparation. By a typical preparation it is understood that it is a preparation that is adapted to be applied to the surface of the eye. In such preparation, the therapeutic compounds of the preparation contact the surface of the eye and penetrate into the deeper tissues of the eye. Usually such preparations have liquid carriers which can be aqueous solutions or suspensions.

Preferably, the muscarinic agents according to the present invention can be provided in formulations that increase the duration of the activity of the muscarinic agent in neuroeffective bonds. Consequently such formulations may include any of the muscarinic agonists and antagonists that were identified above.

The compounds of the present invention can be applied in a pharmaceutically acceptable ophthalmic preparation, which means a preparation that produces medically desirable therapeutic effects without concurrently causing clinically significant adverse effects. Clinically significant effects refer to unacceptable side effects of the preparation, including medically or cosmetically acceptable effects. Examples of unacceptable side effects include redness or irritation of the eyes, impaired vision for long distances, elevated intraocular pressure, or frontal pain.

With particular reference to pilocarpine, the doses used in the present invention fall below the which could cause side effects.

The compounds of the present invention are administered in therapeutically effective amounts. A therapeutically effective amount is that which causes a restoration of the resting position of the eye and allows negative positive normal accommodation. The compounds are added to the ophthalmic preparations of the invention typically at concentrations between 0.001% and 4% by weight of the total formulation.

The compounds of the present invention are preferably administered in a typical manner and are delivered in a medically acceptable, substantially sterile, non-irritating ophthalmic preparation. Ophthalmic preparations may routinely contain pharmaceutically acceptable concentrations of salts, buffering agents, preservatives, viscosity modifiers, osmotic agents, and enhancement agents.

Salts that can be used include but are not limited to sodium chloride, zinc sulfate, and potassium chloride. Buffers that can be used include but are not limited to benzalkonium chloride and disodium edetate. Viscosity modifiers that can be used include but they are not limited to methyl cellulose, glycerol, and polyethylene glycol. Osmotic agents that can be used include but are not limited to mannitol and sorbitol. The supply enhancing agents that facilitate the delivery of the therapeutic compound of the invention into the aqueous humor include substances that increase the permeability of the cornea, such as surfactants, wetting agents, liposomes, DMSO and the like. A moisturizing agent is a substance that facilitates corneal penetration by slightly breaking the external corneal surface. A preferred wetting agent is benzalkonium chloride. Other examples of wetting agents include sorbitan esters, and polyoxyethylene ethers.

It should be understood that although specific formulations have been defined, various modifications are possible. In all cases, the ophthalmic formulations useful in the eye are non-irritating and do not cause harm to the eye in the preferred manner, and are effective in providing the desired results. Normally, such formulations can be applied in a liquid carrier, with an aqueous carrier being preferred, although in some cases, drugs can be administered in rapidly dissolving forms such as powders or in the eyes as from Applicators of various types. Spraying the eye, eye drops and other methods of application may be used.

Dosage levels will vary greatly depending on the individual to be treated and the specific medication used. The appropriate dose can be determined without undue experimentation and according to procedures well known to those of ordinary skill in the art.

Humans can be characterized as having an average amplitude of accommodation (measured in diopters) that decreases steadily with age. The methods of the present invention are useful with subjects having a maximum diopter power of 10 or less, preferably with subjects having a maximum diopter power of 6 or less, and more preferably with subjects having a maximum diopter power of 4 or less. less.

It is preferred that the preparations are packaged as sterile solutions in dropper bottles, which are well known in the trade. Other containers, including glasses, can be used. The preparation is preferably packaged with instructions for use in the preparation in the presbyopia treatment, typically directing the use of the preparation to administer 1 or 2 drops of the solution in each eye.

In a specific example of the present invention, a solution can be formulated as follows: Sodium Chloride 0.3%; Disodium Edetate 0.1%; Boric acid 1.0%; Benzalkonium Chloride 0.01%; Sodium hydroxide (adjust to a pH of 6.4) and Water. Pilocarpine is added to the base solution, at a concentration of 0.1% weight / volume.

The above formulation is administered to the eye of a 50-year-old human with presbyopia, which is shown by his reading discomfort, or his inability to read small impressions. Vision is improved after the administration of the eye drops.

When other agonists are replaced by pilocarpine, similar results are obtained.

Although a specific method in accordance with the present invention has already been described herein, for the purpose of illustration of the manner in which the invention can be used as an advantage, it should be appreciated that the invention is not limited thereto. Consequently, any and all Modifications, variations, or equivalent arrangements that may be made by those skilled in the art, should be considered within the scope of the present invention as defined in the appended claims.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (8)

1. The use of a muscarinic receptor antagonist, characterized in that its use is for the manufacture of a medicament for increasing and decreasing the parasympathetic / cholinergic / ciliary tonic contraction in order to restore the resting portion of the eye and allow normal positive and negative accommodation said medicament being administered to a presbyopic subject in an effective amount.
2. The use according to claim 1, characterized in that the medicament is formulated for topical administration to the eye.
3. The use according to claim 2, characterized in that the muscarinic antagonist is selected to act on the Mi receptors of the ciliary muscle.
4. The use according to claim 3, characterized in that the antagonist is selected from the group consisting of Pirenzepine, Telenzepine and (M? / M4) trihexyphenidyl.
5. 5. The use according to claim 2, characterized in that the muscarinic antagonist is selected to act on the M2 receptors of the ciliary muscle.
6. 6. The use according to claim 5, characterized in that the muscarinic antagonist is selected from the group consisting of (+) (ll- (. {2- [(diethylaminomethyl] -l-piperdidinyl} acetyl) -5, -di- hydro-6H-pyrido (2,3-b) (1,4) benzodiazepin-6-one and (+) 5,11 dihydro-ll- { [2- [(dipropylamino) methyl] -1 - piperidinyl) amino] carbonyl.} - 6H-pyrido (2,3-b) (1,4) benzodiazepin-6-one.
7. 7. The use according to claim 2, characterized in that the muscarinic antagonist is selected to act on the M3 receptors of the ciliary muscle.
8. 8. The use according to claim 7, characterized in that the muscarinic antagonist is selected from the group consisting of diphenylacetoxy-N-methylpiperidine methiodide and (+) p-fluoro-hexahydro-sila-diphenidol hydrochloride. The use according to claim 2, characterized in that the muscarinic antagonist is selected to act on the M4 receptors of the ciliary muscle. The use according to claim 9, characterized in that the muscarinic antagonist is selected from the group consisting of Pirenzepine and Telenzepine.