SK143893A3 - Verapamil hci formulation and other opthalmic solutions with buffer system for ocular administration - Google Patents

Abstract

An aqueous ophthalmic solution is disclosed in which one or more acive ingredients in ionized form are gradually brought to undissociated, free base form by lacrimal solution acting against the affect of a plurality of buffers. The affect of each buffer is overcome sequentially by the lacrimal fluid. A preferred formulation includes verapamil HCl as the active ingredient in ionized form and includes as buffers: boric acid at 2.8 %, disodium edetate at 0.18 %, dextrose at 0.3 %, and polyvinylpyrrolidone at 2.0 %.

Description

Technical field

The invention generally relates to ophthalmic formulations containing the active ingredient.

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BACKGROUND OF THE INVENTION

Ophthalmic solutions are predominantly aqueous based drugs for topical application to the outer surface of the eye. They are indicated for a variety of pathological conditions and are also used as diagnostic agents for visualization of external ocular structures and abnormalities that are not apparent for possible observation by an ophthalmologist.

In connection with the above, the active components of the ophthalmic solutions may include anesthetics, mydriatics (agents that dilate the pupil), miotics (agents that contract the pupil), anti-infectious agents, diagnostics (such as colorants in visualizing invisible areas of the eye surface) surfaces), astringents, demulcentants and lubricants for temporarily alleviating eye problems, as well as anti-inflammatory agents and other ingredients used to enhance specific pharmacological effects.

The essential requirements for an acceptable ophthalmic solution are sterility, clarity and the absence of particles so large as to cause irritation and / or damage to the eye. Furthermore, the aqueous environment of the ophthalmic product should provide an environment that promotes the stability of the active ingredient (s). Furthermore, the resulting ophthalmic solution (active and inactive ingredients) should not be significantly unpleasant after application to the eye. An unpleasant ophthalmic solution has two main disadvantages. First, it does not induce the patient's willingness if used outside a professional intervention, thereby endangering the treatment regimen. Second, the unpleasant ophthalmic solution causes eye irritation, albeit transient, which activates the protective response of the tear. The apparent lacrimation in response to eye irritation is referred to as washout when the body is aware of eye irritation. Unfortunately, if ophthalmic medication is perceived as irritant, the break time is reduced by lacrimation, jeopardizing the desired effect.

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Since pH is one of the mediators of comfort, the focus was on buffering ophthalmic solutions to a pH within a specific range. to provide maximum comfort and maximum practicality of the solution. The pH of normal tear fluid (lacrimal fluid) is approximately 7.2 to 7.4 with variations associated with different pathologies. Significantly uncomfortable conditions occur when the pH exceeds 8 or is below 5. Thus, it has long been considered that if the ophthalmic solutions were adjusted to a pH range approximately the same as normal tears, the resulting solution would be less irritating when used. The discomfort of ophthalmic solutions, if any, is typically related to the properties of the active agent (s). Some chemicals as well as some chemical groups are generally irritating to eye use.

However, in some situations the pH is outside the comfort zone

6.8 - 7.2 necessary to achieve stability and, accordingly, the therapeutic effect of the active ingredient (s) in the formulation. Other active chemicals, not, may still be irritating to properties and profiles. In summary, stable in the pH of the comfort zone due to their dissociation number of ophthalmic drugs, which are uncomfortable for administration, is significant. They include all substances used in professional treatment, in particular mydrics and anesthetics. In addition, it is also uncomfortable for a patient oriented to long-term use of drugs such as pilocarpine HCl or pilocarpine nitrate.

Many ophthalmic preparations thus represent a compromise between two often contradictory requirements: namely the stability of the component and the comfort of the patient. In the past, this com3 promis has been focused on adjusting the pH of the individual formulations in order to find compliance with patient comfort as well as to meet the stability requirements of the substance (s) in the formulation. In the case of necessity and practical application, comfort requirements have always been of lesser importance.

An overview of the dissociation profiles of traditionally uncomfortable ophthalmological preparations serves to demonstrate why their physiological therapeutic efficacy makes the eye uncomfortable. Ophthalmological preparations are physiologically and therapeutically active in their undissociated state (free base). In general, however, their dissociated (ionized) forms (or salts) are used in the preparation of ophthalmic products because they are the most soluble. Examples of ophthalmic preparations that are therapeutically effective in their undissociated form but are formulated as salts are shown in Table 1.

Table 1

Ant ihistami or confer mydriatic antazol in phosphate naphazoline phosphate, pyrilamine maleate, tetrahydrozoline hydrochloride, anesthetics, atropine sulfate, cyclopentolate hydrochloride, homatropine hydrobromide, phenylephrine hydrochloride, scopolamine hydrobromide, anti-inflammatory agents, benoxinate hydrochloride, proparacaine hydrochloride, tetracaine hydrochloride, cromolyn sodium, dexamethasone sodium phosphate, prednisolone sodium phosphate prot [infectious agents, demecarium bromide, echothiophate iodide pilocarpine hydrochloride Pilocarpine Nitrates Gentamycin Sulfate Neomycin Sulfate Polymyxin B Sulfate Sacetacetamide Sodium Timolol Maleate Betaxolol Hydrochloride Verapamil Hydrochloride

Upon application to the outer surface of the eye, these salts are hydrolyzed, resulting in conversion to the free base form and an attached anion or cation. The free base is absorbed by the eye and is primarily responsible for the physiological activity of the drug. Absorption of the free base drug is believed to cause discomfort to the eye. For hydrolytic cleavage of salt. Drugs occur because the eyes maintain a buffering surface pH generally between 7.2 and 7.4. Further distinguishing the pH of the applied ophthalmic preparation from the physiological pH range of the eye causes a faster and more intense hydrolytic activity with possible concomitant acute, intense discomfort. The ionized ophthalmic formulation may be stable in buffer upon storage. However, once the buffering capacity of the drug vehicle is disrupted, the ionized form is immediately transformed into the undissociated form (free base). As a result, intense, acute discomfort occurs with the use of traditional, unambiguous buffers.

Previous ophthalmic drug vehicles have attempted to address the undesired conversion of the dissociated drug to the free base by incorporating chemical buffers known to maintain the ocular surface pH of the formulation for as long as possible. In cases where the pH of the product differs significantly from the pH of the eye surface. these buffers only cause increased inconvenience to the formulation by eliciting an apparent physiological cushioning response by the eye fluid released from the Lacrimal Gland as schematically shown in FIG. First

Recently, it has been found that certain calcium channel blocking agents, particularly verapamil, are capable of reducing elevated intraocular pressure when administered topically to the hypertensive eye in a solution of a suitable ophthalmic vehicle (Abels, US Pat. 4981871, incorporated herein by reference). However, in practice, it has been difficult to obtain an ophthalmic vehicle for verapamil that provides patient comfort.

Verapamil is a classical ophthalmological formulation, stable in the form of its salt (e.g. as verapamil HCl) in an environment with a pH lower than the eye fluid. In order to maintain an appropriate shelf life, the ophthalmologic solution should preferably be maintained in the range of pH 5.0-5.5 by verapam 1-HCl. However, without a suitable buffer vehicle, application of verapamil HCl in a stable form for use on an ocular surface having a physiological pH tear film of the eye (pH 7.0) results in a degree of burning that is unacceptable to the patient.

SUMMARY OF THE INVENTION

More broadly, the present invention is an ophthalmic composition for topical application to the outer surface of the eye, comprising an active agent that causes a pharmacological change in the eye or acts as a diagnostic in the visualization of ocular structures. The active ingredient is applied to the eye in the form of a stable ionized salt at a pH that is relatively lower than the pH of the lacrimal fluid. The active ingredient is active in its undissociated form as the free base at a pH substantially higher than in its di-ionized salt form. The invention also encompasses many buffers in amounts sufficient to prevent an increase in the pH of the active ingredient when it is converted from a salt to a free base in the presence of a lacrimal liquid. Buffers are differentiated by their buffering capacity so that the conversion of the active ingredient from the dissociated form to the free base form is retarded and maintained by subsequent neutralization with various buffers. This gradual formation of the free base provides the patient with significantly greater comfort than in the presence of only one buffer and the change in pH when the active ingredient changes from the dissociated form to the free base form is faster.

More specifically, the invention may use multiple buffers, e.g. three, four, five or more. Such buffers will have different buffering capacity and, if desired, the same total amount. In this way, the pH of the formulation will be at a stage where the buffer capacity of each of the buffers exceeds the capacity of the lacrimal fluid and the pH of the formulation will increase towards the tear pH. More specifically, it is contemplated that multiple buffers, including boric acid, disodium edetate, and polyvinylpyrrolidone (PVP), are the weakest edetate and boric acid is the strongest of weakly associated acids to overcome this capacity. If four buffers are used, the fourth may be dextrose, which is even weaker than edetate and will first be overcome by the user's tears.

In one aspect, the invention relates to an ophthalmic formulation for topical application to the outer surface of the eye comprising verapamil as an active ingredient in the form of a stable, dissociated salt (verapamil HCl) at a pH that is low compared to the pH of the lacrimal fluid. The ophthalmic formulation also includes a buffer system comprising multiple buffers in amounts sufficient to control the increase in pH of the active ingredient as they change from salt to the free base in the presence of a lacrimal fluid. Buffers are distinguished from each other by their buffering capacity so that the conversion of the active ingredient from the dissociated form to the free base form is slowed and maintained by subsequent neutralization with various buffers. This gradual formation of the free base provides the patient with comfort significantly greater than in the presence of only one buffer used, and the change in pH of the active ingredient when changing from the dissociated form to the free base form is faster.

Preferably, the buffers in the buffer system are boric acid at a concentration of 0.5 to 3.0%, most preferably 2.8%; disodium edetate in concentration. 0.08 to 0.5%, most preferably 0.18%; dextrose at a concentration of 0.1 to 5.0%, most preferably 0.3%; and polyvinylpyrrolidone at a concentration of 1.0 to 4.0%, most preferably 2.0%. All concentrations are by weight. The formulation may also contain preservatives, such as benzalkonium and umoride.

The ophthalmic formulation of the invention serves to retard the physiological damping response of lacrimal fluids. In contrast to traditional quenching chemicals which only temporarily adjust the pH of the eye surface to the pH of the formulation but then immediately discontinue this effect by ocular fluids, the formulation of the invention provides a sustained, controlled, descending, shock response. Instead of attempting to maintain a predetermined pH of the ocular surface-oriented product, this allows the ocular pH to be adjusted by lacrimal fluids to about 60

with. For example, it is contemplated that a formulation stored at a pH of about 3 could reach a pH of greater than 6.5 after about one minute after application to the eye and should have a pH of less than 6.5, even less than 6.0 or 5.5, 30. s after application. This sudden change in pH enables a sustained rather than immediate conversion of the dissociated drug to the undissociated form.

By eliminating the immediate conversion of the ionized substance, the preparation allows the gradual conversion of the dissociated form to the non-dissociated form, which forms the absorbable form of the active substance. Slower conversion results in a lower concentration of undissociated drug in the eye at any time, thereby reducing or preventing the discomfort associated with the undissociated drug. Because the eye is less irritated or not irritated at all, the tear response is reduced, allowing longer time for both the eye and the ocular surface.

Other features and advantages of the invention will be apparent from the following description of the preferred embodiment and from the claims of the accompanying drawings, in which: FIG. 1 shows the relationship of traditional buffer-drug combinations to discomfort, and FIG. 2 represents the relationship of discomfort and drug in the buffer system of the invention.

The lacrimal activated buffer system (LABS) of the invention is designed to control (retard) the physiological buffer response of lacrimal fluids to the pH of prepared ophthalmic solutions containing certain active ingredients. Unlike traditional buffered formulations that only temporarily adjust the ocular surface pH to the pH of the product, but then immediately disrupt, when occluded by ocular fluids, the LABS is formulated to provide a sustained, controlled, descending shock buffer response. Instead of attempting to maintain a predetermined pH of the ocular surface-oriented product, LABS provides continuous adjustment of the ocular pH with lacrimal fluids for a period of up to about 60 seconds. This implies that this sudden change in pH allows a permanent rather than an immediate conversion of the dissociated (ionized) form of the active substance to its undissociated (non-ionized) form. By eliminating the immediate conversion of any ionized product, for example verapamil HCl, the measured change in the LABS-induced pH of the eye environment allows for a gradual conversion of the dissociated form into an undissociated, absorbable, therapeutically active form (e.g. verapamil) as schematically shown in FIG. 2. This slower conversion results in a lower concentration of undissociated drug on the eye at any time, thereby reducing or eliminating the discomfort caused by its presence. Because the eye is less irritated or not at all irritated, the tear response is diminished or not, thereby allowing an additional time to medicate the ocular surface with the undissociated drug.

The controlled shift in the equilibrium reaction of the dissociated / undissociated active agent is mediated by the formulation of a formulation that utilizes more and a variety of weak acidic substances which consequently are only slightly dissociated in an aqueous medium. Most commonly, these weakly dissociated acidic substances and their preferred concentrations include, but are not limited to:

boric acid, USP quality (0.5 - 3.0%) disodium edetate, USP quality (0.08-0.5%) t dextrose, USP quality (0.1 - 5.0%) • r. polyvinylpyrrolidone, USP quality (0.1-5.0%).

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All of the above ingredients are known and acceptable for ophthalmic pharmaceutical formulations and, in fact, are used in many available pharmaceutical formulations. However, they are used for other reasons than those described herein. For example, boric acid has antimicrobial and unambiguous pH-adjusting properties when used alone, disodium edetate and dextrose can chemically stabilize some of the ophthalmically active ingredients, and furthermore disodium edetate exhibits an antimicrobial activity. PVP is typically included in viscosity enhancers and / or serves as a suspending agent.

While concentrations outside the preferred ranges are also effective for influencing the dissociation rates of some active ophthalmic components, these concentrations are preferred. It is preferred that all four of these buffer components be used together; however, the use of at least two buffer compounds in a specific formulation is consistent with providing controlled dissociation of certain active ingredients.

The number of buffers and their concentrations are generally related to the discomfort caused by the specific active ingredient. In addition, other organic and / or inorganic substances may be used instead of some or all of the aforementioned conventional buffers. These buffers have the greatest use mainly because they are known to be safe for ophthalmic use.

For example, other weak dissociating acidic substances, such as alginic acid, cyclamic acid, calcium disodium edetate, gluronic acid and sorbic acid, may be used at appropriate concentrations in the compositions of the present invention.

Similarly, the simultaneous use of a strong base such as sodium hydroxide and / or a strong acid such as hydrochloric acid is possible for inclusion in preferred embodiments to bring the formulation into the appropriate final form of the pH range for optimal shelf life.

In addition, pharmaceutically acceptable antimicrobially active preservatives may be included. Examples of compatible preservatives include, but are not limited to, benzalkonium chloride, disodium edetate, phenyl mercurynitrate, silver protein salts, sorbic acid, and thiomersal. From the above list, it is clear that certain agents may perform a dual function of preservative and buffer. The choice of preservative depends on the active ingredients present and the profile of the buffers used.

In a preferred embodiment of the present invention, the LABS formulation is used to act as a comfort vehicle for verapamil HCl, and preferred concentrations of buffer components are as follows:

boric acid 2.8% disodium edetate 0.18% dextrose 0.3%

PVP 2,0%

Additionally, benzalkonium chloride (BAC) is included in the preferred LABS formulation. BAC serves as an antimicrobial agent to maintain sterility of the packaged solution in multi-dose containers. If the solution is packaged as a unit of use (disposable containers), the BAC is discarded from the formulation because it does not adhere to the flexible buffering properties of the formulation.

The mechanism of action of the LABS formulation is based on the capacity of its components to be buffering up to the physiological pH range of the eye fluids with the concomitantly unpleasant active ingredient (s). Due to the weakly acidic nature of the chemicals, each of the LABS components offers a different degree of resistance to ophthalmic damping activity. The LABS component having the weakest resistance (least buffering properties) is neutralized first. Neutralization of the other buffering agents continues from the second weakest to the component having the highest resistance to pH change. Specifically, if four conventional buffers are present in a preferred embodiment, the theoretical order of neutralization of the formulation is as follows:

dextrose --- disodium edetate --- PVP-- boric acid (weakest ------------------------ strongest) relative to their in vitro buffering capacities.

Therefore, as each LABS component is neutralized (buffered to about pH 7.0), the pH of the eye fluids gradually increases. As the pH increases (or decreases acidity), the more dissociated product is concentrated, e.g. verapamil HCl, hydrolytically to an undissociated product, e.g. absorbable free base of verapamil. Because this conversion is retarded and maintained by the gradual neutralization of the LABS components (shock buffer phenomenon), eye discomfort associated with immediate, total conversion to the free base is usually reduced or eliminated. The average free base concentration gradually increases as the pH of the ocular surface increases (due to neutralization of the LABS components) until it reaches its maximum concentration and then decreases. This is because the buffers used must be qualitatively and quantitatively selected to match the dissociation profile of the active ingredients present in the specific formulation.

At the same time, there are three factors that help to eliminate the apparent concentration of free base on the eye surface:

1) as the free base forms, it is absorbed from the eye surface into the inner tissue of the eye,

2) the tear film activity constantly removes the drug from the ocular surface; and

(3) the free principle is established gradually.

The first two phenomena are common in the application of all eye drops, and there is a third phenomenon that distinguishes the activity of LABS from other buffer formulations used to prevent ocular formulations from causing discomfort.

The buffer system of the invention can be precisely designed to conveniently receive a specific ophthalmic formulation by adjusting the concentration of each buffer and changing the number of buffers. As a result, an almost infinite number of comfort models can be used to effect a controlled conversion of the dissociated drug to the undissociated drug. The degree of comfort that is required is a function of the association profile of the active ingredients with respect to the characteristics and the degree of free base formed in an environment approximately equal to or slightly below pH 7. The stability of the vast majority of active ophthalmic ingredients is increased over this pH range. Thus, the pharmaceutical product can be adjusted to a pH in the range in which it is guaranteed even though it is well below the pH of the eye. As a result, stability and comfort requirements can be addressed without compromising each other.

In another embodiment, the ophthalmic solution of the invention may be considered a race drug solution in an aqueous ophthalmic vehicle comprising an amount of ophthalmologically acceptable acidifying agent sufficient to maintain the solution at an acidic pH in the range of 4.5 to 5.5 during storage and an amount of ophthalmologically acceptable buffer having a range. The pH between the pH of the solution and the normal pH of the mammal's eye sufficient to cause the pH of the ophthalmic fluid to gradually return to its normal value after application of the ophthalmic vehicle dose to the eye.

The ophthalmic vehicle of the invention can be used to formulate drugs for topical administration to the eye when, for reasons of stability, the active ingredients have been stored at. relatively low pH, but are only significantly absorbed from solutions close to physiological pH.

As a result, the ophthalmic solution of the present invention will contain an acidifying agent, often referred to in the art as a buffer, which will adjust the pH of the vehicle to a range suitable for long-term storage of the active ingredient, typically pH 4.5-5.5. The acidifying agent will typically be a weak acid such as boric acid, sorbic acid or the like.

The ophthalmic solution of the invention will comprise one or more intermediate buffers, i. compounds having a buffering capacity at. the pH between the acidic pH to which the vehicle is adjusted for the long-term stability of the active ingredient and the normal pH of the eye, i. 7.2 to 7.4. A buffer solution, as is well known to those skilled in the art, is one in which there will be relatively small changes in pH when an acid or base is added thereto. Buffer solutions typically comprise an aqueous solution of a substance that can react with added acid or base to prevent rapid change in pH at. addition of an acid or base. The theory and practical use of buffers is well known. A preferred buffer may be a mixture of a weak acid and a salt thereof, i. partially neutralized weak acids. Typically, such compositions exhibit a maximum of their buffering capacity, i.e. their greatest resistance to change in pH by the added acid or base, at a pH at which the acid is about half neutralized. However, buffers may include materials, e.g. water-soluble polymers or organic compounds for which the theory of their buffering capacity cannot be so easily expressed mathematically. Nevertheless, these materials can be evaluated experimentally and characterized by their resistance to change in pH when the acid or base is added to the aqueous solution containing it. Thus, one of ordinary skill in the art can readily select suitable buffering materials for use in the compositions of the invention. For example, a practitioner may select a buffer mixture derived from a weak acid that will be partially neutralized to the desired pH of the buffer, i. acids having a pKa very close to the selected buffer pH. Alternatively, the practitioner may utilize known properties of water-soluble polymers such as poly (vinylpyrrolidone) or organic compounds such as dextrose.

Obviously, the practitioner may select one or more ophthalmologically acceptable buffer materials and adjust their concentration in the ophthalmic solution to achieve the desired gradual neutralization when administered to the eye. Multiple intermediate buffers may be used, each having an effective buffering action at different pHs ranging from the acidic pH at which the ophthalmic solution is maintained to increase its shelf life and the normal pH of the eye, i.e. ranging from about

4.5 to about 7.2. In such a buffer mixture, the pH will gradually increase as the eye gradually neutralizes each buffer material.

Preferred materials useful in the ophthalmic vehicle of the invention include boric acid as the oxidizing agent and as intermediate buffers, sodium dibasic edetate, dextrose and poly (vinylpyrrolidone) (PVP). Of such buffers, PVP was found to have significant buffering capacity at pH between the original acidic pH of the vehicle, i. about 4.5 to 5.5 and the pH of the lacrimal fluids, i. 7.2 to 7.4. Similarly, disodium edetate having a pKa in this range will be considered to have a buffering capacity in this pH range. Dextrose can be used as a buffer in a pH range weakly acidic relative to the natural pH of lacrimal fluids.

Other ophthalmologically acceptable buffers may also be used in the vehicles of the invention, e.g. phosphate buffers and citrate buffers, as well as other weakly dissociating acidic substances such as alginic acid, cyclamic acid, sodium calcium edetate, giycuronic acid, sorbic acid and the like.

The amount of intermediate buffer incorporated into the ophthalmic vehicle of the invention should be sufficient to provide sufficient buffering capacity to induce a relatively slow return of the precoreal lacrimal fluid to normal physiological pH. The duration of this gradual increase in pH chosen for a particular drug will depend on the particular drug used, the concentration of drug required for therapeutic purposes, and the tendency of the drug to elicit discomfort. A typical duration of about 60 seconds will provide a time long enough for substantial drug absorption while keeping the instantaneous free base concentration so small as to minimize discomfort. However, longer or shorter duration may be affected by adjusting the concentration of intermediate buffers. The choice of the concentration of intermediate buffers for a given drug and its therapeutic concentration is readily determined by the practitioner.

Use of the invention

Verapamil HCl in the LABS buffer formulation can be administered heated to the outer surface of the eye to reduce elevated intraocular pressure. The effective dose employed will vary depending upon the particular patient. However, a typical dose will range from about 10 micrograms to about 1 milligrams per eye per day.

The typical concentration of verapamil HCl in this buffer solution will vary from about 0.1 mg / ml to about 5 mg / ml. Preferably, the concentration of the solution is adjusted to deliver the desired dose of verapamil HCl per drop, e.g. about 40 microliters.

Other embodiments are claimed.

Claims (24)

PATENT CLAIMS An aqueous ophthalmic formulation for topical application to the exterior surface of a mammalian eye for reducing elevated intraocular pressure, comprising verapamil when the verapamil is applied to the eye in the form of a stable, dissociated salt - verapamil HCl at a low pH compared to a pH of the lacrimal fluid of about 7.2-7.4a, a pharmaceutically acceptable ophthalmic vehicle buffered to said pH which is low compared to the pH of the lacrimal fluid, wherein said vehicle is capable of controlling the pH of said composition in a controlled manner in the presence of the lacrimal fluid; the vehicle contains boric acid at a concentration of 0.5 to 3.0%. disodium edetate at a concentration of 0.08 to 0.5%, dextrose at a concentration of 0.1 to 5.0% and polyvinylpyrrolidone at a concentration of 1.0 to 4.0%. The composition of claim 1, wherein the concentration of said boric acid in the vehicle is 2.8%. The composition of claim 1, wherein the concentration of disodium edetate in the vehicle is 0.18%. The composition of claim 1, wherein the concentration of dextrose in the vehicle is 0.3%. The composition of claim 1, wherein the concentration of polyvinylpyrrolidone in the vehicle is 2.0%. 6. The formulation of claim 1 wherein said vehicle is a solution with boric acid concentration of 2.8%, disodium edetate concentration of 0.18%, polyvinylpyrrolidone concentration of 2.0%. The composition of any one of claims 1 to 6, wherein said vehicle further comprises benzalkonium chloride. The formulation of claim 1, wherein said vehicle is a solution and wherein the concentration of verapamil HCl in said solution is such that a therapeutically effective amount of said verapamil HCl can be contained in one drop of said solution - about 40 microliters. An aqueous ophthalmic formulation for topical application to the outer surface of the eye, with reduced discomfort in patients. characterized in that it comprises an active ingredient for effecting a pharmacological change in the eye or for the diagnostic purpose of visualizing the ocular structures, and said active ingredient is applied to the eye in the form of a stable, dissociated salt at a pH which is low compared to a pH of lacrimal fluid of about 7 2 to 7.4, said active ingredient is pharmacologically or diagnostically active in its undissociated form as the free base at a pH substantially higher than its dissociated form as ionized salts and more buffers in an amount sufficient to stop the pH increase of said active ingredient as it changes from free base salts in the presence of said lacrimal fluid, and said buffers differ in their buffering capacities such that the conversion of said active ingredient from the dissociated form to the free base form is retarded by the progressive neutralization of different buffers at different pH levels and the progressive form of the free base γ provides comfort to the patient considerably greater than when only a single buffer is present and the change in pH when the active ingredient moves from the dissociated form to the undissociated is faster. The formulation of claim 9, wherein said buffers are at least three. The composition of claim 10, wherein said buffers are selected from the group consisting of boric acid, disodium edetate, polyvinylpyrrolidone and boric acid. Composition according to claim 11, characterized in that said buffers are boric acid, disodium edetate and polyvinylpyrrolidone. The composition of claim 9, wherein said buffers are at least four. The composition of claim 13, wherein said buffers are boric acid, disodium edetate, polyvinylpyrrolidone and boric acid. An aqueous ophthalmic formulation for topical application to the external surface of the eye, with reduced patient discomfort, comprising an active ingredient selected from the group consisting of antihistamines, anesthetics, miotics, mydriatics, anti-inflammatory agents, anti-infective agents, timolol-maleic , betaxolol HCl and verapamil HCl, said active ingredient being applied to the eye in the form of a stable, dissociated salt at a pH that is low relative to the pH of a lacrimal fluid of about 7.2 to 7.4, said active ingredient being pharmacologically or diagnostically effective in its undissociated form as the free base at a pH substantially higher than its dissociated form as the ionized salt and more buffers in amounts sufficient to stop the pH of said active ingredient from changing from salt to free base in the presence of a lacrimal fluid, said buffers they differ from each other in their buffering capacity such that the conversion of said active ingredient from the dissociated form to the free base form is retarded by the progressive neutralization of the various buffers at different pH levels and the progressive free base formation provides the patient with significantly greater comfort than when only one buffer is present. from the dissociated form to the non-dissociated form is faster. 16. The formulation of claim 15, wherein said buffers are at least three. 17. The composition of claim 16, wherein said buffers are selected from the group consisting of boric acid. disodium edetate, polyvinylpyrrolidone and boric acid. The formulation of claim 15, wherein said buffers are present in substantially equal amounts. The composition of claim 15, wherein the pH of said solution prior to administration is about 3. The formulation of claim 19, wherein the pH of said solution one minute after application is greater than 6.5. The formulation of claim 20, wherein the pH of said solution 30 seconds after application is less than 6.5. ₅ 22. An aqueous ophthalmic formulation for topical administration to a mammalian eye comprising an ophthalmic drug in a vehicle comprising an aqueous solution comprising an amount of an ophthalmologically acceptable acidifying agent sufficient to maintain said solution in an acidic range of pH 4.5 to 5; 5 during storage and an amount of an ophthalmologically acceptable buffer having a buffered pH range between the pH of the solution and the normal pH of the mammal tears sufficient to induce gradual neutralization of the vehicle with tears of the eye when the ophthalmic vehicle dose is applied to the eye. 23. Use of an aqueous solution comprising an ophthalmic drug in an aqueous vehicle, comprising an amount of an ophthalmologically acceptable acidifying agent sufficient to maintain said solution at an acidic pH of between 4.5 and 5.5 during storage and an amount of an ophthalmologically acceptable buffer having a buffered pH range between pH of the solution and normal pH of the mammal's eye, sufficient to induce gradual neutralization of the vehicle with the tears of the eye when the ophthalmic vehicle dose is applied to the eye, for the treatment of ophthalmic conditions by topical administration of said solution to the eye. The use according to claim 23, wherein said medicament is verapamil hydrochloride and said solution is used for the treatment of glaucoma.