JPH06511014A - Ophthalmic solutions, such as verapamil hydrochloride formulations containing a buffer system, for administration to the eye - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Ophthalmic solutions, such as verapamil hydrochloride formulations containing a buffer system, used for injection into the eye agent Technical field of invention The present invention generally relates to ophthalmic compositions containing active ingredients.

Background of the invention Ophthalmic solutions are primarily water-based solutions designed for topical application to the outer surface of the eye. It is a medicine. This solution is readily apparent during routine observation by the eye care physician. In addition to being used as a diagnostic aid to visualize structures and abnormalities outside the eye, Used for pathological conditions in species.

Therefore, the active ingredients of ophthalmic solutions include paralytic drugs, mydriatic drugs (drugs that dilate the pupils), drugs), miotic drugs (medications that constrict the pupils), anti-infective drugs, diagnostic drugs (medications that constrict the pupils), (such as dyes that visualize ocular surface areas and other surface abnormalities), astringent drugs, and ocular discomfort. Specific pharmacological effects of demulcents, lubricants, and anti-inflammatory agents that temporarily reduce sensation There are ingredients that have been designed to bring about this.

The basic product-related requirements for acceptable ophthalmic solutions are sterility, transparency, contain particles large enough to cause irritation and/or eye damage (N. There is no such thing. Moreover, the aqueous excipients of ophthalmic products are stable to the active ingredients. must provide an environment that promotes Furthermore, the obtained ophthalmic solution (active ingredients and inactive ingredients) should not be significantly unpleasant when administered to the eye. unpleasant Ophthalmic solutions have two major drawbacks. First, used outside of professional settings Treatment schedules sometimes do not promote patient compliance results are at risk. Second, unpleasant ophthalmic solutions may cause temporary eye irritation. giving, triggering an excessive tearful protective response. Apparent tearing in response to eye irritation is designed to flush out what the body perceives as eye irritants. a If an ophthalmic drug is recognized as an irritant, its residence time in the eye may be reduced to tears. thus, the desired effect is impaired.

One factor in comfort is pH, so it is important to keep ophthalmic solutions within a specific pH range. Traditionally, emphasis has been placed on buffering fluids to provide maximum comfort and longest service life. has been looked at. The pH of normal tear fluid (lacrimal fluid) is approximately 7.2 to 7.4; Changes are associated with different pathologies.

Significant discomfort occurs when the pH exceeds 8 or falls below 5. Therefore If the ophthalmic solution is adjusted to a pH range close to that of normal tears, the resulting drug has long been claimed to be less irritating when used. Is the discomfort caused by the ophthalmic solution? When this occurs, it is generally related to the properties of the active ingredient. certain chemical agents and certain chemical groups are generally irritating when applied to the eye.

However, in some cases, pH ranges outside the "comfort zone" of 6.8 to 7.2 may result in poor stability. and is therefore necessary to ensure the therapeutic effect of the active ingredients in the formulation. of pH Other chemical agents that are stable in the comfort zone may differ due to their dissociative properties and profile. May cause irritation. Overall and 12, which ophthalmic drugs cause discomfort when instilled into the eyes? There are quite a few. Most of these drugs are used in professional settings. These include, in particular, mydriatics and anesthetics. On top of that, give it to patients for a long time. For example, pilocarpine hydrochloride or pilocarpine nitrate used over a long period of time is also prohibited. It's pleasant.

Therefore, many ophthalmic formulations have two seemingly non-conflicting requirements: thus representing a compromise between component stability and patient comfort. Historically, this compromise Attempting to address the patient's desire for comfort and the need for stability of ingredients in the formulation have focused on adjusting the pH of specific formulations to meet Necessity and practicality ``The question of comfort has always been of lesser importance.

Reconsidering the dissociative properties of traditionally unpleasant ophthalmic drugs is important in improving the physiology of these drugs. The ophthalmic and therapeutic activity helps explain why ocular discomfort occurs. Ophthalmic drugs are It is physiologically and therapeutically active in its free base (free base) state. but, When formulating ophthalmic products, the dissociated (ionized) form (if (or salt) is used because it is the most soluble. Therapeutically in its undissociated form Ophthalmic drugs that are active but formulated as salts are shown in Table 1.

Table 1 Antazoline/Phosphate Atropine/Naphazoline Sulfate/Phosphate Cyclohent Rade hydrochloric acid Homatropine/bromic acid Pyrylamine/maleic acid, phenylephrine, tetrahydrozoline, scopolamine ・bromic acid Anesthetics Anti-inflammatory drugs Benoxinate / Hydrochloric acid Cromolyn sodium Proparacaine / Hydrochloric acid Dexame Tazone sodium tetracaine/hydrochloric acid/prednisolone sodium phosphoric acid Miotic drugs, anti-infective drugs Demecarium bromide, gentamicin, sulfuric acid iodide ecothiophate, neomycin Pilocarpine sulfate, hydrochloric acid, polymyxin, bilocarpine sulfate, nitric acid fuacetamide sodium others Timolol maleic acid Betaxolol/hydrochloric acid Verapamil/hydrochloric acid When applied to the outer surface of the eye, these salts “hydrolyze” into their free base form. Instead, an anion or a cation is attached. This free base is absorbed through the eye. and finally bring about the biological activity of the drug. Causes of discomfort to the eyes It is the absorption of free base drugs that is recognized as Hydrolytic release of pharmaceutical salts The buffering capacity of the eye should be such that the eye maintains its surface pH at approximately 7.2-7.4. This happens because you have. The pH of the applied ophthalmic product or the eye As we move away from the physiological pH range, its hydrolytic activity becomes more rapid and It becomes intense and is accompanied by acute and intense discomfort. Ionized ophthalmic products are stored in buffer solutions. It is stable inside. However, once the buffering capacity of a pharmaceutical excipient is “broken”, it becomes ionized. The converted form “instantly converts to the unresolved 1!II (free base) form.

Therefore, the use of traditional non-compromising buffers may result in more intense and acute discomfort. be done.

Conventional ophthalmic drug excipients maintain the pH of the ocular surface for as long as possible. By mixing non-compromising chemical buffers designed to maintain the product pH91. Attempts have been made to address the discomfort of converting the dissociated drug to the free base. It's here. If the pn of the product differs significantly from the ocular pH, such buffers should be As shown diagrammatically in This only increases the discomfort with the product by provoking reactions.

Recently, certain calcium channel blockers, particularly verapamil, have been introduced with appropriate ophthalmic preparations. When dissolved in a formulation and administered topically to hypertensive eyes, it lowers high intraocular pressure. (Abelson, U.S. Pat. No. 4,981.871) No. 3', which is hereby incorporated by reference in this application). However, patient compliance It is virtually difficult to obtain an ophthalmic excipient for verapamil that guarantees there were.

Verapamil is administered in salt form (e.g. verapamil) in an environment with a pH lower than the pH of tear fluid. It is an important ophthalmological drug that is stable in hydrochloric acid. To maintain a reasonable shelf life , the ophthalmic solution of verapamil/hydrochloric acid is preferably 5. () ~ Maintain a pH of 5°5. must be tlied. However, without proper buffering excipients, verapamil Add hydrochloric acid in a storage-stable form to the surface of the eye [the physiological pH of the lachrymal membrane (pH 7.0)]. ] may cause severe pain that is unbearable for the patient to comply with the medication. be done.

Summary of the invention In broad applicability, the present invention is an ophthalmic composition for topical application to the outer surface of the eye, which Activity as a diagnostic aid to induce pharmacological changes or to clarify ocular structures Ingredients can be freely selected. The active ingredient is an ion that is stable at a pH lower than that of tear fluid. It is instilled in the form of salt. The active ingredient is dissolved as an ionized salt. It is 11ζ-prone as a free salt in its undissociated form at a pH significantly higher than the pH. Ru. Also, the active ingredient is extracted from salt in the presence of lachrymal fluid; III! Active when changing to lI base A constant buffering agent is present in a sufficient amount to prevent the pH of the chemical components from rising. It's happening. These buffers differ greatly in their buffering performance, and therefore the active ingredient Conversion from the dissociated form to the free base form is achieved by sequential neutralization of different buffers. Soothed and sustained by.

This gradual formation of free base means that only a single buffer is used and the active compound is The change in pH when changing from the isolated form to the free base form is more rapid. It also provides the patient with a significantly better sense of comfort.

More specifically, the present invention provides for a plurality of buffers, e.g., 3, 4, 5FL. It is contemplated that L or more buffers may be used. Such a buffer is They have different buffering performance, and if desired the sum=1 amount is the same. In this way the composition The pH of the composition is determined by the buffering capacity of each buffer being overcome by the pH of the composition. Proceed to the stage of ``-4 toward the pH of tears''. To be more specific, Hou acid, edetate, and polyvinylpyrrolidone (P■P) It is conceivable to use a buffer of Detate is the weakest and boric acid is the most powerful. In case 1 uses 4 types of buffers, Kistrose is the No. 4 [1] slow-Wli agent. Dextrose is nib 1-acid. It is even weaker, so it will be destroyed first by the tears of the Ministry of Use.

In another aspect, the present invention provides a dissociated salt ( External surface of the eye containing verapamil as active ingredient in the form of verapamil (hydrochloric acid) This is an ophthalmological composition for topical application. This ophthalmological The composition also changes when the active ingredient changes from the salt to the free base in the presence of lachrymal fluid. Contains a buffer system consisting of multiple buffers in an amount sufficient to suppress the increase in PTI of are doing. These buffers differ in their buffering performance from each other, resulting in less dissociation of the active ingredient. The conversion from the ``ii1 free base form'' to the ``ii1 free base form'' is ameliorated by sequential neutralization of different buffers. It lasts a long time. This gradual formation of free base means that only a single buffer The active ingredient used changes more rapidly from the dissociated form to the free base form. Give the patient better comfort than before.

The buffer in this buffer system preferably has a boric acid concentration of 05-3.0%, which is most preferred. Preferably, it is 2.8%; the concentration of edetate disodium is 0.08 to 0.5%. Most preferably [, L18%; dextrose concentration 0, 1. -5 , 096 TeRmo! Ir*L, <Ha0, 396; and The concentration of polyvinylpyrrolidone is 1.0-4.0%, most preferably 2.0%. Ru. All these concentrations are in weight percent. Also, even if the composition contains preservatives, Often and most preferred is benzalkonium chloride.

The ophthalmic compositions of the present invention serve to moderate the physiological buffering response of lachrymal fluid. surface of the eye The pH of the product is adjusted to the l)H level of the product for a very short time, and as soon as L1 is overthrown by lachrymal fluid, Unlike traditional buffering chemicals that "break", the compositions of the present invention are sustained and controlled. Trenched buffer response that is controlled and degraded I do. ) Attempts to maintain a defined, product-oriented pH environment on the surface of the eye. Instead, the compositions of the invention reduce the pH of the eye due to lachrymal fluid for up to about 60 seconds. It can be done over a period of time. For example, a composition stored at a pH of about 3: A pH greater than 6°5 is reached in about 1 minute after instillation, and 30 seconds after instillation. The pH becomes less than 6.5 and further becomes less than 6.0 or 5°0. this Conversion of 'C1-dissociated drug to undissociated form by trenched pH change It does not take place immediately, but on a continuous basis.

By avoiding instantaneous conversion of all ionized drugs, the present invention The composition gradually converts the active agent from a dissociated form to a non-dissociated absorbable form. . Since the conversion takes place slowly, the degree of a of the undissociated drug in the eye is always low, resulting in Undissociated drug: 1+ discomfort is reduced or avoided. My eyes are too irritated Because the person does not perceive the sensation at all, the response to produce tears decreases, and as a result, the drug's Residence time on the ocular surface increases.

Other features and features of the invention can be found in the above description of the preferred embodiments of the invention; It will become clear from the inversion of claim 1 and the accompanying drawings below.

Figure 1 shows the traditional buffer-medication discomfort relationship, and FIG. 2 shows the medicament-induced discomfort relationship of the buffer system of the present invention.

Description of preferred embodiments The lachrymal activated buffer system (LABS) of the present invention contains certain active ingredients. Suppresses (relaxes) the physiological buffering response of tear fluid caused by the pH of the stored eye f1 solution. (depending on the situation). Simply change the pH of the eye surface to the pn of the product for a short time. Unlike traditional buffering compositions, which adjust quickly and “break” quickly when overwhelmed by lachrymal fluid, LABS is designed to provide a “trenched” buffer response that is suppressed and degraded over time. has been prescribed. Keep the ocular surface in a predetermined product-friendly pH environment. Instead of trying to reduce the pH of the eye over a period lasting up to about 60 seconds, LABS is constantly made into an R node by tear fluid. As a result, this 1 non-chipped 13H The change causes the dissociated form (ionized form) and undissociated form (non-ionized form) of the active ingredient. The transformation into (form) is not instantaneous but continuous. An example of an ionized product is Vera. By avoiding instantaneous conversion of the entire pamil-hydrochloric acid, LABS induced ocular pl (due to regulated changes in the environment, as shown schematically in Figure 2). , gradually from its dissociated form to its undissociated, absorbable, therapeutically active form (e.g. verapamil). The conversion can be performed separately. These slow transformations cause the eye to The concentration of undissociated drug in the Discomfort is reduced or avoided.

The eyes rarely, if ever, notice any irritation, so the tearful response is reduced. or disappear, thereby increasing the residence time of undissociated drug on the ocular surface. be able to.

The suppressed shift in the dissociation/undissociated equilibrium reaction of the active ingredient is due to the The product is manufactured using a selected number and type of weakly acidic chemical agents that only slowly dissociate. mediated by agents. These weakly dissociated acidic chemical agents and their preferred concentration ranges are , although not limited to cases such as F are the most common.

Boric acid, USP clade (0.5-3.0%), Nina I-lium edetate, US Pharmacopoeia grade (0.08-0.596), Dextrose, US 1rJ Pharmacopeia grade (0.1~5°0%), Polyvinylpyrrolidone (PVP), USP clade (1,0~40%) .

All of the above ingredients are approved and accepted for use in ophthalmic pharmaceutical formulations, and in fact many Used in commercially available ophthalmic preparations. However, these drugs contain This is due to other reasons and is not relevant to its use as described in this application. For example boric acid When used in the medium, it has antibacterial and non-compromising pH-regulating properties and is Dextrose and dextrose can chemically stabilize certain ophthalmically active ingredients. , moreover, edetate disodium exhibits antibacterial activity. PVP generally increases viscosity and/or included in the formulation to serve as a suspending agent.

Concentrations outside the preferred range affect the dissociation rate of some active ophthalmic ingredients! The above range is currently the preferred concentration, although it is not without its beneficial effects. column It is preferred to use all four buffer compounds listed together, but in certain formulations By using at least two of these buffer compounds, the dissociation of a given active ingredient can be similarly achieved. suppressed.

The number and concentration of buffering agents is generally related to the discomfort imparted by a particular active ingredient. be. In addition, other organic and/or inorganic chemical agents may be added to the conventional buffers listed. can be used in place of some or all of i'+'l It will be recognized. Are these buffers safe for use in ophthalmic formulations? Most of them are the most used because they are recognized as such.

For example, other weakly dissociated acidic substances such as alginic acid, nuclamin acid, calcium edetate disodium, glucuronic acid and turubilic acid. It can be used at a concentration suitable for light formulations.

Additionally, a strong base such as sodium hydroxide and/or a strong acid such as hydrochloric acid may be added to the When used, the formulations of the present invention may be prepared at the appropriate final stage for optimal storage stability. Preferred embodiments include maintaining the pH within the range of .

Second, it may contain an antibacterial preservative that can be used as a pharmaceutical agent. of mutuality Examples of preservatives include, but are not limited to, hensalkonium mide, edelate disodium, phenylmercuric nitrate, protein silver salts, sorbic acid and thimerosal Ru. It is important to note that some drugs act dually as preservatives and buffers. It should be clear from the strike. The selection of preservatives depends on the active ingredients present and the It depends on the tube of buffer used.

In a preferred embodiment of the invention, the LABS formulation is directed against verapamil hydrochloride. The preferred concentration of the buffer component used to act as a comfort excipient is: It is a cage.

Boric acid 2.8% Edetate thorium 0.18% Dextrose 3% PVP 2.0% Furthermore, henzalkonium chloride (BAC) is included in the preferred LABS formulation. There is. BAC has been installed many times! antibacterial agents that maintain the sterility of drugs packaged in containers for useful as. The liquid drug is packaged in a unit-of-use container. BAC should be removed from the formulation.

This is due to the compliant buffering properties of the formulation.

The mechanism of action of LABS formulations is that the physiological pH range of the lachrymal fluid is associated with the “unpleasant” active ingredient. It is based on the performance of its components that are buffered up to. Presence of weakly acidic chemical agents In addition, each component of LABS exhibits a different weak resistance to the buffering activity of tear fluid. most The components of LABS that have the weakest resistance (least buffering properties) are neutralized first.

Neutralization of the other buffer components ranges from the second least resistant to changes in pH to the p Continue to the component with the greatest resistance to changes in H. To be specific, I prefer Theoretical order of neutralization of this formulation if the four common buffers of the new embodiment are present. The introduction is as follows. That is, based on the in vitro buffering capacity of those buffers, Dextro→edetate disodium→PVP→boric acid (weakest to strongest) be.

Therefore, as each component of LAB S is neutralized (buffered to pH 7.0), The pH of the lachrymal fluid gradually increases. As this pH increases ( i.e. as the acidity decreases), dissociated products such as verapamil hydrochloric acid may be hydrolyzed to an undissociated product, e.g. verapamil free base, which can be absorbed. converted. This conversion reaction is ameliorated by successive neutralization of LABS components. (trench buffering phenomenon), resulting in instantaneous total conversion to free base. The associated ocular discomfort is largely reduced or eliminated. The pH of the ocular surface is (LAB As the component of S increases (as the S content is neutralized), the average concentration of free base increases up to It gradually increases until the concentration is reached and then decreases. Therefore, it is natural that multiple loose Buffers have qualitative and quantitative effects on the dissociated form of the active ingredient present in a particular formulation. special specifications must be made.

Three factors work to help avoid the apparent concentration of free base on the ocular surface. and at the same time.

1) As the free base is formed, it is absorbed from the ocular surface into the internal tissues of the eye; 2) Due to the activity of the tear film, pharmaceutical products are constantly removed from the ocular surface; and 3) Free base is formed gradually.

The first two phenomena are common to all eye drops, but the third phenomenon is , the activity of LABS can be compared with other buffering compounds used to add comfort to ophthalmic formulations. This is a phenomenon that distinguishes it from other products.

Therefore, the buffer system of the present invention allows the concentration of each buffer to be adjusted for one week and the number of buffers to be varied. By customizing certain ophthalmic formulations, it is possible to can.

As a result, there are infinite possibilities to suppress the conversion of dissociated drug to undissociated drug. It is possible to devise a number of "patterns of comfort". The level of comfort required is Characteristics and extent of free base formation in environments with a pH near or somewhat below 7. is a function of the dissociated form of the active ingredient. Stability of most active ophthalmic ingredients is enhanced within this I)H range. Therefore, pharmaceutical products must have a pH that is The pH should be adjusted to a range that ensures long-term stability, even if it is significantly lower than the pH. Can be done. Therefore, the prerequisites for stability and a feeling of comfort are that neither can detract from the other. It is possible to solve both.

In an embodiment of the present invention, the ophthalmic solution of the present invention has a concentration of 4.5 to 5.5% during storage. an ophthalmologically acceptable acidifying agent, or an ophthalmologically acceptable acidifying agent, sufficient to maintain an acidic pH in the range of 5. After instilling a single dose of ophthalmic excipients, the tear PL is gradually increased to its normal value. A sufficient amount to restore the pH range between the pH of the solution and the normal pH of the mammalian eye. Dissolve the drug in an aqueous ophthalmological excipient containing an ophthalmologically acceptable buffering agent with It is considered an aqueous solution.

The ophthalmic excipients of the present invention are such that the active ingredients are stored at a relatively low pH to achieve stability. If it is absorbed significantly only from solutions close to physiological pH, it may be harmful to the eye. It can be used to administer topically administered medicines.

Therefore, the ophthalmic solution of the present invention has a pH of the excipient suitable for long-term storage of the active ingredient. Acidifying agents (according to the art These acidifying agents are Generally, it is a weak acid such as boric acid or sorbic acid.

The ophthalmic solutions of the present invention contain one or more intermediate buffers, i.e. excipients that are longer than the active ingredient. Normal pH of the eye with acidic r+H adjusted to obtain stability for a period of time i.e. 7. Contains compounds with pH buffering capacity between 2 and 7°4.

Buffer solutions are well known to those skilled in the art, A solution that experiences a relatively small change in pH when an acid or base is added to it. It's itl. Buffer solutions generally react with added acids or bases to form acids or bases. is a water-soluble substance that prevents the pH from changing rapidly when a base is added. It is made of liquid (R).

The theory and practice of using buffering agents is well known.

Suitable buffers are mixtures of weak acids and their salts, i.e. partially neutralized weak acids. Ru. Generally, such mixtures have a pH at which the acid is approximately 1/2 neutralized. with the highest buffering capacity, i.e. the change in pH caused by the added acid or base. Shows maximum resistance to deterioration. However, buffering agents such as water-soluble polymers or Contains substances whose buffering capacity theory cannot be easily expressed mathematically, such as organic compounds or organic compounds. are doing. Nevertheless, such substances can be dissolved in aqueous solutions containing them. Experiments on resistance to changes in pH when acids or bases are added [ can be investigated and characterized. Therefore, those skilled in the art will appreciate the use of the compositions of the present invention. A suitable buffer substance can be easily immobilized. For example, one skilled in the art can determine the desired A weak acid partially neutralized by mild WipH, i.e. a selective edge? ! fii p H An acid-derived buffer mixture can be selected that has a plc a value close to a. a Alternatively, those skilled in the art will appreciate that water-soluble polymers such as poly(vinylpyrrolidone) or Organic compounds such as storose may also be used.

Obviously, one skilled in the art will be able to select one or more ophthalmologically compatible buffer substances and The concentration of substances in ophthalmic solutions can be adjusted to achieve the desired effect when these substances are instilled into the eye. Gradual neutralization can be achieved. In particular, multiple intermediate buffers may be used. Each of these buffers is used to retain the ophthalmic ITL agent in order to increase its shelf life. acidic pn to ocular IE within the normal pH range, i.e. in the range of about 4.5 to about 7.2. It has an effective buffering effect at different pH within the range. In buffer mixtures such as The pH of is gradually raised 1 F as the eye neutralizes each buffer sequentially.

Preferred substances that can be used in the ophthalmic preparation of the present invention include fluorophore as an acidifying agent. Uric acid, and edetate disodium as an intermediate buffer, dextrose, or and poly(vinylpyrrolidone) (PVP). The length of these buffers , PVP is the initial acidity of the excipient r>H i.e. about 4.5-5.5 and the lachrymal fluid It has been found that a pH between 7°2 and 7.4 has a significant buffering capacity. Served. Similarly, edetate disodium has a pKa value within the above range. is considered to have a buffering capacity within this PL range.Similarly, dextrose It can be used as a buffer in a pH range that is slightly more acidic than the natural pH of tear fluid. Wear.

Other ophthalmologically acceptable buffers can also be used in the excipients of the present invention. , such as phosphate and citrate buffers, as well as alginic acid, shiframi acid, calcium disodium butate, glucuronic acid, and sorbic acid. There are other weakly dissociative acidic substances such as

The amount of intermediate buffering agent mixed into the ophthalmic excipients of the present invention is such that the precorneal lachrymal fluid is The amount should be sufficient to provide sufficient buffering capacity to return to the physiological pH relatively slowly. Must be. This gradual increase in the pH selected for a particular drug The period of time required for treatment depends on the specific drug used, the concentration of drug required for therapeutic purposes, and It depends on the nature of the medicine causing the eye discomfort. Generally, the period of approximately 60 seconds is medicinal product while preserving the instantaneous concentration of free base, short enough to minimize discomfort. provide a sufficiently long period of time for substantial absorption. However, longer than this period or shorter periods can also be carried out by adjusting the concentration of intermediate buffers. . Selection of intermediate buffering agent concentrations and therapeutic concentrations for a given drug is within the skill of those skilled in the art. This is an easy decision.

Purpose Verapamil hydrochloride in a LABS buffer composition is topically administered to the outer surface of the eye to Elevated intraocular pressure can be lowered. Effective stage used! j amount depends on the specific patient It varies depending on. However, a typical dosage is about 10 per eye per - It is in the range of μg to about 1 mg.

The concentration of helabamyl/hydrochloric acid in the buffer solution is approximately 0. img/ml to approximately 5 mg /ml. Preferably, the concentration of the solution is -drops, e.g. about 40 μI is adjusted to dispense the desired dose of verapamil hydrochloride.

Other implementations are within the scope of the claims.

Continuation of front page (51) Int, C1,5 identification symbol Internal office reference number A61K 47/36 B 7433-4C (31) Priority claim number (32) Priority mill March 18, 1993 (33) Priority claim country United States (US) FI (81) Designated countries EP (AT, BE, CH, DE.

DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE) , 0A (BF, BJ, CF, CG, CL CM, GA, GN, ML, MR, SN , T.D.

TG), AT, AU, BB, BG, BR, CA, CH.

CZ, DE, DK, ES, FI, GB, HU, JP, KP, KR, LK, LU, MG, MN, MW, NL, N.

, NZ, PL, PT, RO, RU, SD, SE, SK.

A

Claims (24)

[Claims] 1. An aqueous ophthalmological drug that is administered topically to the outer surface of the eye during the nursing period to reduce increased intraocular pressure. A composition comprising: a stable dissociation at a pH lower than that of tear fluid of about 7.2 to 7.4; verapamil applied to the eye in the form of salt (verapamil hydrochloric acid), and buffered at said pH that is lower than the pH of tear fluid, such that the pH of said composition in the presence of tear fluid is It consists of a pharmaceutically acceptable ophthalmological excipient that can suppress the increase in The excipients include boric acid at a concentration of 0.5-3.0%, boric acid at a concentration of 0.08-0.5%. edetate disodium, dextrose at a concentration of 0.1-5.0%, and 1. An aqueous ophthalmic composition consisting of polyvinylpyrrolidone at a concentration of 0 to 4.0%. 2. The composition of claim 1, wherein the concentration of boric acid in the excipient is 2.8%. thing. 3. The concentration of the disodium edetate in the excipient is 0.18%. The composition according to claim 1. 4. Claim 1, wherein the concentration of said dextrose in said excipient is 0.3%. composition. 5. A claim wherein the concentration of the polyvinylpyrrolidone in the excipient is 2.0%. Item 1. The composition according to item 1. 6. the excipient is a solution and the concentration of the boric acid is 2.8%; The concentration of disodium torate is 0.18%, the concentration of the dextrose is 0.3%, and the concentration of said polyvinylpyrrolidone is 2.0%. . 7. Claims 1 to 6, wherein the excipient further contains benzalkonium chloride. A composition according to any one of the above. 8. the excipient is a solution, and the concentration of verapamil hydrochloric acid in the solution; contains a therapeutically effective amount of verapamil hydrochloride in one drop of about 40 μl of the solution. 2. A composition according to claim 1, wherein the composition is at such a concentration that it may have 9. An aqueous ophthalmic composition for topical application to the outer surface of the eye that reduces patient discomfort. There it is; Activity as a diagnostic aid to produce pharmacological changes in the eye or to visualize ocular structures component, wherein the active component has a pH of about 7.2 to 7.4 relative to the pH of tear fluid. applied to the eye in the form of a dissociated salt that is stable at low pH; The pH is significantly higher than when the active ingredient is in its dissociated form as an ionized salt. pharmacologically or diagnostically active when in undissociated form as a free base at low pH; , and when the active ingredient is converted from the salt to the free base in the presence of the tear fluid. containing a plurality of buffering agents in an amount sufficient to suppress the increase in pH of the active ingredient; Buffers differ from each other in their buffering performance, resulting in a loss of release from the dissociated form of the active ingredient. Conversion to the free base form sequentially neutralizes different buffers at different pH levels by the gradual formation of the free base, a single Because only a buffer was used, the active ingredient transitions from the dissociated form to the undissociated form. provides a significantly greater sense of comfort to the patient than when the pH changes are more rapid; Aqueous ophthalmic composition. 10. 10. The composition of claim 9, wherein the number of buffers is at least three. 11. The buffering agent comprises boric acid, edetate disodium, PVP and boric acid. 11. The composition according to claim 10, wherein the composition is selected from the group consisting of: 12. Claim 1 wherein said buffering agent is boric acid, edetate disodium and PVP. 1. The composition according to item 1. 13. 10. The composition of claim 9, wherein the number of buffers is at least four. 14. The buffering agent is boric acid, edetate disodium, PVP and boric acid. The composition according to claim 13. 15. Aqueous ophthalmic composition for topical application to the outer surface of the eye that reduces patient discomfort And; Antihistamines, anesthetics, mydriatic drugs, miotic drugs, anti-inflammatory drugs, anti-infective drugs, Consisting of timolol maleate, betaxolol/hydrochloric acid and verapamil/hydrochloric acid containing an active ingredient selected from the group; The active ingredient is stably dissociated at a pH lower than that of the filtrate, which is about 7.2 to 7.4. applied to the eye in the form of a salt, and the active ingredient dissociates as an ionized salt. In its undissociated form as a free base at a pH significantly higher than that in is diagnostically active, and the active ingredient is purified from the free base salt in the presence of the lachrymal fluid. Multiple buffering agents in sufficient amounts to suppress the increase in active ingredient pH when changing to The buffering agents differ from each other in their buffering performance, and as a result, the active ingredient The conversion of the dissociated form to the free base form occurs sequentially with different buffers at different pH levels. It is then relieved by neutralization, which leads to the gradual formation of the free base. Therefore, because only a single buffer was used, the active ingredient was separated from the dissociated form to the undissociated form. The patient experiences significantly greater comfort than when the pH changes are more rapid when transitioning to the give, Aqueous ophthalmic composition. 16. 16. The composition of claim 15, wherein the number of buffers is at least three. 17. The buffering agent comprises boric acid, edetate disodium, PVP and boric acid. 17. The composition according to claim 16, wherein the composition is selected from the group consisting of: 18. 16. The composition of claim 15, wherein said buffering agents are present in approximately equal amounts. 19. 16. The composition of claim 15, wherein the pH of the solution before instillation is about 3. 20. 20. The pH of the solution 1 minute after instillation is higher than 6.5. Composition of. 21. 21. The pH of the solution 30 seconds after instillation is lower than 6.5. Composition of. 22. Contains an ophthalmic drug in an excipient consisting of an aqueous solution, and administers the drug topically to the mammalian eye. An aqueous ophthalmic composition for use in administering; The aqueous solution is Sufficient amount of ophthalmology to maintain itself at an acidic pH in the range of 4.5 to 5.5 during storage an acidifying agent acceptable above, and When a single dose of ophthalmic excipient is instilled into the eye, the excipient is slowly absorbed by the tears in the eye. between the pH of the solution and the normal pH of the mammalian eye in an amount sufficient to neutralize the an ophthalmologically acceptable buffer having a pH buffering range of Composition. 23. By topical administration to the eye of an aqueous solution containing an ophthalmic drug in an aqueous buffer. A use of the aqueous solution for treating ophthalmological conditions; an amount sufficient so that the aqueous solution maintains an acidic pH in the range of 4.5 to 5.5 during storage; an ophthalmologically acceptable acidifying agent, and When instilling a single dose of ophthalmic excipients, the excipients are gradually absorbed by the tears in the eye. a pH buffer between the pH of the solution and the normal pH of the mammalian eye in an amount sufficient to An ophthalmologically acceptable buffering agent having a negative range. 24. The drug is verapamil hydrochloride, and the solution is used for the treatment of glaucoma. 24. The use according to claim 23.