CN112007031A

CN112007031A - Ophthalmic preparation

Info

Publication number: CN112007031A
Application number: CN201910463854.6A
Authority: CN
Inventors: 林书毅
Original assignee: Syncore Biotechnology Co ltd
Current assignee: Syncore Biotechnology Co ltd
Priority date: 2019-05-30
Filing date: 2019-05-30
Publication date: 2020-12-01
Also published as: KR20200138648A

Abstract

The present disclosure relates to an ophthalmic formulation composition to provide a stable hydralazine topical formulation for the treatment of ocular diseases and conditions comprising 0.02 to 2% by weight of a hydralazine pharmaceutically active drug; wherein the chelating agent does not substantially contain ethylenediamine tetraacetic acid ion for chelating metal ion. The present disclosure also relates to methods of preparing the above ophthalmic compositions.

Description

Ophthalmic preparation

Technical Field

The present disclosure provides ophthalmic formulations and methods of treatment of the eye.

Background

Hydralazine is a known hypotensive drug that produces a hypotensive effect by relaxing the vasodilatory action of vascular smooth muscle. More specifically, hydralazine alters calcium metabolism, thereby interfering with calcium mobilization in vascular smooth muscle, thereby affecting the onset or prolongation of the contractile state of vascular smooth muscle: (

A package insert).

In addition to the medical use of lowering blood pressure, U.S. patent 8,088,773, which is incorporated herein by reference, teaches hydralazine for the treatment of non-neovascular or dry age-related macular degeneration. Age-related macular degeneration is a chronic disease that causes the loss of vision in older adults over 60 years of age in developed countries. The disease is mainly divided into two forms, dry and wet. Dry is the early stage of the disease, visual deterioration is related to the generation of cryptic junctions (mains) in the Retinal Pigment Epithelium (RPE), wet is the development of the disease to the late stage, and the disease process is mainly characterized by Choroidal Neovascularization (CNV) which is characterized by abnormal vascular proliferation of choroidal membranes, and the abnormally proliferated blood vessels are easy to rupture and bleed, and are continuously deteriorated to cause visual deterioration.

Aqueous hydralazine hydrochloride solutions may undergo degradation during storage to form strongly colored insoluble products. The stability of the aqueous hydralazine hydrochloride solution was found to be related to the pH of the solution. The stability of the aqueous hydralazine hydrochloride solutions at various pH values (pH 1 to 12) was tested and found to be the best storage stability of hydralazine in an environment of pH 3.5 (Halasi et al, 1990, J Parenter Sci technol.,44(1): 30-4.).

Hydralazine discolors when it contacts the metal. As with other hydrazine derivatives, hydralazine reacts with oxygen and metal ions such as Cu²⁺、Fe² ⁺And Fe³⁺Can be oxidized to free radicals (Sinha et al, 1982, Biochemical and Biophysical Research Communications 105 (3): 1044-1051). To address this problem, it is common practice to add a chelating agent to improve stability. For example, both U.S. Pat. Nos. 5,185,372 and 6,468,548 teach the use of chelating agents to improve stability. In chinese patent CN102813621A, EDTA chelating agent is added to solve the stability problem in order to increase the stability of the solution.

U.S. patent 9,254,287, incorporated herein by reference, discloses a hydralazine hydrochloride ophthalmic composition for the treatment of age-related macular degeneration. Chelating agents are included in the ophthalmic formulation composition regimens of this patent to chelate metal ions. The use of chelating agents makes the formulation cost high. However, even the hydralazine hydrochloride aqueous solution added with the chelating agent still cannot avoid the problem of solution discoloration, and great troubles are brought to the storage and the use of the preparation. This problem has not been solved well.

Disclosure of Invention

In one aspect, the present disclosure provides an ophthalmic composition to provide a stable hydralazine topical formulation for the treatment of ocular diseases and conditions comprising 0.02 to 2% by weight of a hydralazine pharmaceutically active drug; wherein the chelating agent does not substantially contain ethylenediamine tetraacetic acid ion for chelating metal ion.

In some embodiments, the composition has a pH between 4.0 and 4.4 and maintains a colorless, transparent, clear upon storage at a temperature above 50 ℃ for four weeks.

In one embodiment, the ophthalmic composition comprises a therapeutically effective amount of a hydralazine pharmaceutically active drug, one or more buffering agents, isotonic agents and preservatives, wherein no chelating agents are present. In accordance with other embodiments of the present disclosure, the ophthalmic composition may further comprise one or more of a lubricant, a pH adjuster, a viscosity enhancer, a diluent, and the like, as appropriate.

In another embodiment, an ophthalmic composition comprises hydralazine pharmaceutically active drug in an amount between about 0.02 to 2% by weight, acetate buffer solution at a pH between 3.9 to 4.5 in an amount between 8 to 12% by weight, sodium chloride in an amount between 0.25 to 1% by weight, methyl paraben in an amount between 0.015 to 0.06% by weight, and benzalkonium chloride solution in an amount between 0.01 to 0.04% by weight.

In another embodiment, the pharmaceutically active drug is hydralazine hydrochloride, which is present in an amount between 0.5 to 2% by weight.

In another embodiment, the acetate buffer solution has a pH of about 3.5 to 4.5, 3.5 to 4.2, 3.5 to 4.0, 3.8 to 4.4, or 4.0 to 4.5 and is present in an amount of 10 wt%.

In one embodiment, the acetate buffer solution consists of sodium acetate and 2N acetic acid.

In another embodiment, the benzalkonium chloride solution concentration is 50%.

In one embodiment, the composition further comprises 0.5 to 2% by weight propylene glycol, preferably propylene glycol is present in an amount of about 1% by weight. In another embodiment, methylparaben is present in an amount of about 0.03 weight percent. In yet another embodiment, the benzalkonium chloride solution is present in an amount of about 0.02% by weight.

The present disclosure provides an ophthalmic composition to provide a stable topical hydralazine formulation for the treatment of ocular diseases and conditions comprising: 0.02 to 2% by weight of a hydralazine pharmaceutically active drug; 8 to 12% by weight of an acetate buffer solution having a concentration of 2N; 0.25 to 1 weight percent sodium chloride; 0.015 to 0.06% by weight of methyl paraben; and 0.01 to 0.04 wt% benzalkonium chloride solution at a concentration of 50%; wherein the chelating agent does not substantially contain ethylenediamine tetraacetic acid ion for chelating metal ion.

The ophthalmic composition as described above, wherein the acetate buffer solution has a pH of about 3.5 to 4.5, 3.5 to 4.2, 3.5 to 4.0, 3.8 to 4.4, or 4.0 to 4.5 and is present in an amount of 10 wt%.

The ophthalmic composition as described above, wherein the acetate buffer solution consists of sodium acetate and 2N acetic acid.

In one embodiment, the pharmaceutically active drug is hydralazine hydrochloride, which is present in an amount between 0.5 to 2% by weight.

In one embodiment, the ophthalmic composition further comprises 0.5 to 2% by weight propylene glycol.

In one embodiment, the propylene glycol content of the ophthalmic composition is 1% by weight.

In one embodiment, the methylparaben content of the ophthalmic composition is 0.03 weight percent.

In one embodiment, the benzalkonium chloride solution is present in the ophthalmic composition in an amount of 0.02% by weight.

In another aspect, the present disclosure provides methods of preparing an ophthalmic composition. In one embodiment, the method comprises mixing a diluent and one or more buffer solutions having a pH between about 3.5 and 4.5 to form a first temporary mixture, adding one or more isotonic agents to the first temporary mixture to form a second temporary mixture, adding one or more preservatives to the second temporary mixture to form a third temporary mixture, and adding a pharmaceutically active drug comprising hydralazine to the third temporary mixture to form an ophthalmic formulation.

In one embodiment, the method comprises mixing a diluent and one or more buffer solutions having a pH between about 3.5 and 4.5 to form a first temporary mixture, adding one or more lubricants to the first temporary mixture to form a second temporary mixture, adding one or more isotonic agents to the second temporary mixture to form a third temporary mixture, adding one or more preservatives to the third temporary mixture to form a fourth temporary mixture, and adding a pharmaceutically active drug comprising hydralazine to the fourth temporary mixture to form an ophthalmic formulation.

In one embodiment, the buffer is an acetate buffer solution having a pH of about 3.9 to 4.5, added in an amount to provide between about 8 to 12 weight percent of the acetate buffer solution in the composition. In another embodiment, the acetate buffer solution is added in an amount to provide about 10% by weight acetate buffer in the formulation. In a further embodiment, the acetate buffer solution consists of sodium acetate and 2N acetic acid.

In one embodiment, the lubricant is propylene glycol added in an amount to provide between about 0.5 to 2% by weight of propylene glycol in the formulation. In a further embodiment, the propylene glycol is added in an amount to provide about 1% by weight propylene glycol in the composition.

In a further embodiment, the isotonic agent is sodium chloride added in an amount to provide between about 0.25 to 1% by weight of sodium chloride in the composition. In one embodiment, the sodium chloride is added in an amount to provide about 0.5% by weight sodium chloride in the composition.

In yet another embodiment, the preservative is benzalkonium chloride added in an amount to provide between about 0.01 to 0.04% by weight benzalkonium chloride in the composition. In another embodiment, the benzalkonium chloride solution is added in an amount to provide a solution of about 0.02% by weight benzalkonium chloride in the composition. In a further embodiment, a second preservative is added, wherein the second preservative is methyl paraben added in an amount to provide between about 0.015 to 0.06 percent by weight of methyl paraben in the composition. In yet another embodiment, the methylparaben is added in an amount to provide about 0.03 weight percent methylparaben in the composition.

In embodiments, the pharmaceutically active drug is hydralazine present in the composition between about 0.5 to 2% by weight. In a further embodiment, the pharmaceutically active drug is hydralazine hydrochloride. In a specific embodiment, the pharmaceutically active agent is hydralazine hydrochloride present in the composition at about 1% by weight.

In embodiments, the one or more adding steps further comprise mixing while adding.

In another aspect, the present disclosure provides a method for treating macular degeneration. In embodiments, the method comprises administering a therapeutically effective amount of an ophthalmic composition described herein to the eye of a subject at risk of or diagnosed with macular degeneration. In one embodiment, the macular degeneration is age-related macular degeneration. In a specific embodiment, the age-related macular degeneration is dry age-related macular degeneration.

Detailed Description

To make the objects, technical solutions and advantages of the embodiments of the present disclosure more apparent, the embodiments of the present disclosure will be described in detail and completely, it is to be understood that the embodiments described are only a part of the embodiments of the present disclosure, and not all embodiments may be provided. All other embodiments that can be derived by one of ordinary skill in the art from the embodiments disclosed herein without making any creative effort fall within the scope of the present disclosure.

The definitions of terms that may appear in the present disclosure are as follows:

the term "subject" as used herein means a mammal, such as a human or an animal.

Concentrations, amounts, pH, and the like are generally presented as ranges and should not be construed as an immutable limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have explicitly disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, a description of a pH range such as 3.8 to 4.4 should be considered to have explicitly disclosed sub-ranges such as 3.8 to 4.4, 3.8 to 4.2, 3.8 to 4.0, 4.0 to 4.4, 4.2 to 4.4, 3.9 to 4.2, 4.0 to 4.2, and the like, as well as individual values within that range, such as 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, and 4.4.

By "therapeutically effective amount" is meant an amount of pharmaceutically active drug or drug that is useful in preventing, treating, or slowing the progression of a vision disorder or impairment of vision or an eye disease.

References herein to "pharmaceutically active drug", "drug", or any particular composition or compound referred to by name, such as hydralazine, include pharmacologically active compounds and pharmaceutically acceptable salts thereof. Salts of the pharmacologically active drug may be derived from acids, examples including, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, and phosphoric acid.

According to one embodiment of the present disclosure, an ophthalmic composition comprises a hydralazine pharmaceutically active drug, one or more buffering agents, isotonic agents, and preservatives, wherein the chelating agent is absent. The chelating agent has one or more multidentate ligands that provide pairs of electrons to form coordinate bonds with the center. For example, the ethylenediaminetetraacetic acid ion of formula I provides 6 coordinate bonds to the metal (M) with 2 nitrogen atoms and 4 carboxyl oxygen atoms:

the present disclosure finds that, unlike the teachings found in the prior art, the addition of a chelating agent to ophthalmic compositions comprising hydralazine does not improve stability, solving the problem of discoloration. Further, contrary to the expectation of one of ordinary skill in the art, hydralazine ophthalmic compositions that do not contain a chelating agent have greater stability and are able to solve the problem of discoloration during storage and use. Accordingly, the hydralazine ophthalmic compositions of the present disclosure that do not include a chelating agent are not only less costly but also have greater stability.

In some embodiments, ophthalmic compositions comprising hydralazine of the present disclosure are substantially free of ethylenediaminetetraacetic acid ions for chelating metal ions. In some embodiments, ophthalmic compositions of the present disclosure comprising hydralazine do not include disodium edetate, tetrasodium edetate, and disodium edetate dihydrate.

Suitable buffering agents are known in the art and include, without limitation, acetate, ascorbate, tris, sodium acetate trihydrate, acetic acid, citrate buffers, borate, carbonate, acetate, and/or phosphate. The pH of the ophthalmic solution generally ranges from about 3.0 to 7.7, with the pH of most ophthalmic solutions being about 5 to 7. In embodiments, the pH of the formulations of the present disclosure is between about 3.0 to 7.7 or about 5 to 7. In preferred embodiments, the pH of the ophthalmic solution is about 3.5 to 4.5, 3.5 to 4.2, 3.5 to 4.0, 3.8 to 4.4, or 4.0 to 4.5. It will be appreciated that the buffer used will depend on the pH to be maintained. In other embodiments, a pH adjusting agent may also be utilized to adjust the pH of the formulation. It will be appreciated that any pH modifying agent known in the art and suitable for topical administration to the eye may be used. In non-limiting embodiments, the pH adjusting agent is selected from sodium hydroxide and/or hydrochloric acid. Exemplary buffers include sodium acetate trihydrate USP (united states pharmacopeia) and acetic acid USP (2N). An additional exemplary buffer is acetate buffer solution USP comprising sodium acetate trihydrate USP and acetic acid USP.

Isotonic agents are generally agents or compounds that are physiologically tolerated and impart to the formulation a suitable tonicity to prevent the net diffusion of water across the cell membrane in contact with the formulation. Suitable isotonic agents include, but are not limited to, salts (including sodium chloride) and sugars (e.g., dextrose and lactose). The osmolality of the eye is about 290 mOsmol/kg. The osmolality of the ophthalmic solution typically ranges from about 250 to 350mOsmol/kg, the majority of which falls between about 290 and 300 mOsmol/kg. In embodiments, the osmolality of the formulations of the present disclosure should be at or near the osmolality of the eye. In specific non-limiting embodiments, the osmolality of the formulations of the present disclosure is generally between about 250 to 350mOsmol/kg or between about 290 to 300 mOsmol/kg. In a specific embodiment, the osmolality of the formulation of the present disclosure is about 300 mOsmol/kg. An exemplary isotonic agent is sodium chloride USP.

In one embodiment, the pH of the composition is between about 3.5 and 4.5. In a preferred embodiment, the pH of the composition is between about 3.8 and 4.4. In another embodiment, the pH of the composition is between about 4.0 and 4.4.

Suitable preservatives are known in the art and include, but are not limited to, benzalkonium chloride, methyl paraben (methylparaben), chlorobutanol, thimerol (thimerol), propylparaben, and polyquaternium-1 (polyquaternium-1). According to FDA Advisory Review Panel on OTC opthalmic Drug Products (date 1979 Final report 12), benzalkonium chloride USP was used in Ophthalmic formulations at a maximum concentration of 0.013% and methylparaben NF at a maximum concentration of 0.1-0.2%. Benzalkonium chloride USP is most active against bacteria, but is believed to be less potent against pseudomonas and mold. Methylparaben NF is most active against fungi and gram-positive bacteria, but is considered to be less active against gram-negative bacteria. Exemplary preservatives include benzalkonium chloride NF and/or methyl paraben NF.

In accordance with other embodiments of the present disclosure, the ophthalmic composition may further comprise one or more of a lubricant, a pH adjuster, a diluent, a viscosity enhancer, and the like, as appropriate.

Suitable lubricants include, but are not limited to, propylene glycol, polyethylene glycol, polyvinyl alcohol, and glycerin. An exemplary lubricant is propylene glycol USP.

Suitable diluents are known in the art and include, but are not limited to, purified water USP and water for injection. Exemplary diluents include water, especially water for injection USP and saline.

Suitable viscosity enhancing agents are known in the art and include, but are not limited to, polyvinyl alcohol, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.

Clinically, repeated doses of topical hydralazine hydrochloride formulations are safe and well tolerated for age-related macular degeneration subjects (Ralston et al, 2010, ARVO extracts, abstract number 913/a 196). In some embodiments, the methods described herein relate to preventing or slowing the progression of age-related macular degeneration with a composition described herein. In one embodiment, a method of preventing or slowing choroidal neovascularization in a patient diagnosed with non-exudative or exudative age-related macular degeneration using a formulation described herein is contemplated.

In one embodiment, a 1% by weight hydralazine ophthalmic solution is instilled in the eyes of a subject at least once daily, and in other embodiments, between one and five times daily. In yet another embodiment, the 0.5 to 4 weight percent hydralazine ophthalmic solution is instilled in the eye of the subject at least once daily, and in other embodiments, one to five times daily. In further embodiments, the 0.5 to 2 weight percent hydralazine ophthalmic solution is instilled in the eye of the subject at least once daily, and in other embodiments, one to five times daily.

The following examples illustrate exemplary methods provided herein. These examples are not intended to, and should not be construed as, limiting the scope of the disclosure. It will be apparent that the methods may be practiced otherwise than as specifically described herein. Numerous modifications and variations are possible in light of the teaching herein, and it is therefore within the scope of the disclosure.

Example (b): example 1: the formulations may be prepared by stepwise addition of the ingredients.

In an embodiment, a method of preparing an ophthalmic composition formulation comprises: firstly, a proper amount of buffer solution is added into a proper amount of purified water under stirring. Purified water is preferably filled into a container of suitable size to accommodate the volume of the final formulation. The buffer solution may be prepared separately or may be commercially available. In one non-limiting embodiment, the buffer solution is an acetate buffer solution. In one non-limiting embodiment, the acetate buffer solution comprises sodium acetate, acetic acid, and purified water. In an exemplary embodiment, the acetate buffer solution has a pH of about 4.2 to 4.6. In a specific embodiment, the pH of the buffer is 4.2. By way of non-limiting example, an acetate buffer solution may be prepared by adding 1.75g of sodium acetate and 18.6mL of acetic acid 2N to a 1L volumetric flask, supplemented to 1000mL with the appropriate amount of purified water. The pH of this exemplary buffer solution should be about 4.2.

One or more lubricants are added to the buffer solution while stirring. The resulting solution a is mixed until the lubricant is completely or almost dissolved. In one non-limiting embodiment, the lubricant is propylene glycol. One or more isotonic agents are added to solution a while stirring. The resulting solution B is mixed until the isotonic agent is completely or almost completely dissolved. One or more preservatives are added to solution B while stirring. The resulting solution C is mixed until the preservative is completely or almost completely dissolved. One or more therapeutic agents (including but not limited to hydralazine hydrochloride) are added to solution C while stirring. The resulting solution D is mixed until the therapeutic agent is completely or nearly completely dissolved.

It will be appreciated that where more than one type of ingredient is used (e.g. two or more preservatives), the ingredients may be added together or separately. Where the ingredients are added separately, the solution may be mixed thoroughly or nearly thoroughly before the next ingredient is added. In this process, formulation parameters may be measured and the formulation adjusted accordingly. For example, the pH can be measured and adjusted if desired.

Table 1 and table 2 show 8 specific formulations of ophthalmic formulations comprising hydralazine according to embodiments of the present disclosure, which are designated as formulation a-formulation h, respectively. Wherein, all the components are added according to the mass percentage. The entire mass percentage of the preparation may be supplemented to 100% by using a diluent, or a mixed solution of a diluent and a viscosity enhancer, or the like, as the case may be.

As shown in tables 1 and 2, formulations a-e all gave clear, colorless solutions, while formulations f-h initially gave solutions that were colored.

TABLE 1

TABLE 2

Example 2: the stability of the formulations of the present disclosure was tested by accelerating the chemical or physical changes of the drug by increasing the storage temperature.

The 8 hydralazine hydrochloride formulations of formulation a to formulation h in example 1 were filled into glass sample vials. The formulations were stored at 40 ℃ and 50 ℃ to evaluate storage under accelerated chemical or physical changes of the drug. The pH, osmolality (Osmol/kg) and content (%) of the active ingredient of the solution were measured at times of zero and one, two, three, four weeks and the appearance and color of the solution were observed.

Results as shown in tables 3 to 10, the hydralazine hydrochloride formulations of formulation f, formulation g and formulation h already discolored at room temperature. The formulations a, b, c, d and e remained colorless, clear and transparent when stored at 40 ℃ for four weeks. Upon storage at 50 ℃ for three weeks, formulations a, b and c had discolored; however, unexpectedly only formulations d and e remained colorless, clear and transparent when stored at 50 ℃ for four weeks.

Table 3: stability test results of formulation a over time

Table 4: stability test results of formulation b over time

Table 5: stability test results of formulation c over time

Table 6: stability test results of formulation d over time

Table 7: results of stability test of formulation e over time

Table 8: results of testing the stability of formulation f over time

Table 9: stability test results of formulation g over time

Table 10: formula h stability over time test results

As can be seen from the above examples, the pH has an effect on the stability of the formulation. The initial state of formulation f-formulation h is already discolored. In some embodiments, the pH of the formulations of the present disclosure is about 3.5 to 4.5, 3.5 to 4.2, 3.5 to 4.0, 3.8 to 4.4, or 4.0 to 4.5.

Further, it can be seen from the above examples that whether a chelating agent is included also has an influence on the stability of the formulation. Contrary to the teachings in the art, the addition of chelating agents does not improve the stability of the formulation. Surprisingly, formulations d and e, without the addition of a chelating agent, had better stability than formulations a-c, with the addition of a chelating agent; the product can be stored at 50 deg.C for 4 weeks and still maintain colorless, transparent and clear state.

As one of ordinary skill in the art will appreciate, "comprising" herein means including, but not limited to, and allowing for the inclusion of unspecified elements, steps, ingredients, or components. By "substantially free" is meant that the amount of the specified ingredient or component is no greater than 0.001%, as measured.

Unless otherwise indicated, all numbers expressing quantities of ingredients, properties, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure. When further clarified, the term "about" when used in conjunction with a listed value or range means more or slightly less than the listed value or range to within ± 20% of the listed value; 19% of the listed values; . + -. 18% of the values listed; . + -. 17% of the values listed; . + -. 16% of the values listed; . + -. 15% of the values listed; . + -. 14% of the values listed; 13% of the listed values; 12% of the listed values; 11% of the listed values; . + -. 10% of the values listed; . + -. 9% of the values listed; . + -. 8% of the values listed; . + -. 7% of the values listed; . + -. 6% of the values listed; . + -. 5% of the values listed; . + -. 4% of the values listed; . + -. 3% of the values listed; . + -. 2% of the values listed; or. + -. 1% of the values listed.

Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, contains the inherent degree of specific error that must be attributed to the standard deviation found in its corresponding testing measurement.

The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. Any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to further illuminate the invention and does not pose a limitation on the scope of the claims.

The specific aspects described herein, including the best mode known to the inventors for carrying out the invention. Variations of those described aspects may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this disclosure is intended to cover all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the disclosure unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

1. An ophthalmic composition comprising 0.02 to 2% by weight of a hydralazine pharmaceutically active drug; wherein the chelating agent does not substantially contain ethylenediamine tetraacetic acid ion for chelating metal ion.

2. The ophthalmic composition of claim 1 wherein the pH of the composition is between 4.0 and 4.4 and remains clear and colorless over four weeks of storage at a temperature above 50 ℃.

3. An ophthalmic composition comprising:

0.02 to 2% by weight of a hydralazine pharmaceutically active drug;

8 to 12% by weight of an acetate buffer solution having a concentration of 2N;

0.25 to 1 weight percent sodium chloride;

0.015 to 0.06% by weight of methyl paraben; and

0.01 to 0.04% by weight of a benzalkonium chloride solution having a concentration of 50%;

wherein the chelating agent does not substantially contain ethylenediamine tetraacetic acid ion for chelating metal ion.

4. The ophthalmic composition of claim 3, wherein the acetate buffer solution has a pH of about 3.5 to 4.5, 3.5 to 4.2, 3.5 to 4.0, 3.8 to 4.4, or 4.0 to 4.5 and is present in an amount of 10% by weight.

5. The ophthalmic composition of claim 3, wherein the acetate buffer solution consists of sodium acetate and 2N acetic acid.

6. The ophthalmic composition of claim 3, further comprising 0.5 to 2% by weight propylene glycol.

7. The ophthalmic composition of claim 3, wherein the propylene glycol content is 1% by weight.

8. The ophthalmic composition of claim 3, wherein the methylparaben is present in an amount of 0.03 percent by weight.

9. The ophthalmic composition of claim 3, wherein the benzalkonium chloride solution is present in an amount of 0.02% by weight.

10. A method of making an ophthalmic composition comprising mixing water with an acetate buffer solution having a pH of 3.9 to 4.5 in an amount to provide about 8 to 12 wt% of the acetate buffer solution in the composition to form a first intermediate mixture; adding propylene glycol to the first intermediate mixture to form a second intermediate mixture, the propylene glycol being added in an amount to provide about 0.5 to 2% by weight of propylene glycol in the composition; adding sodium chloride to the second intermediate mixture to form a third intermediate mixture, the sodium chloride being added in an amount to provide about 0.25 to 1% by weight of sodium chloride in the composition; adding a benzalkonium chloride solution to the third intermediate mix to form a fourth intermediate mix, the benzalkonium chloride solution being added in an amount to provide from about 0.01 to 0.04% by weight of benzalkonium chloride solution in the composition; adding methyl paraben to the fourth intermediate mixture to form a fifth intermediate mixture, the methyl paraben being added in an amount to provide from about 0.015 to 0.06 percent by weight of methyl paraben in the composition; adding 0.02 to 2 weight percent hydralazine pharmaceutically active drug to the fifth intermediate mixture to form the composition.

11. Use of an ophthalmic composition according to claims 1-9 for the preparation of a medicament for the prevention or treatment of age-related macular degeneration.

12. The use of claim 11, wherein the age-related macular degeneration is dry age-related macular degeneration.