Fixed dose combination of brimonidine and timolol

Abstract

To provide a topical ophthalmologic composition for the treatment of glaucoma, ocular hypertension, and lowered intraocular pressure.SOLUTION: A topical ophthalmologic composition comprises 0.1% w / v brimonidine tartrate and about 0.68% w / v timolol maleate.SELECTED DRAWING: None

Description

Background Art

[0001] Brimonidine and timolol have been formulated as eye drops known to lower intraocular pressure ("IOP") in patients with glaucoma or ocular hypertension. This drug is available as monotherapy at multiple concentrations (brimonidine 0.1%, 0.15%, 0.2%, and timolol 0.25% and 0.5%) in various countries. These drugs are known to be used concomitantly in patients with conditions that cannot be adequately controlled with monotherapy. Formulating a fixed combination product containing brimonidine and timolol provides benefits to patients both in terms of improving the benefit-risk ratio and simplifying the administration of treatment.

Summary of the Invention

[0002] In one embodiment, provided is a composition for the treatment of glaucoma and ocular hypertension, the composition comprising about 0.1% w / v brimonidine tartrate and about 0.68% w / v timolol maleate and being configured for topical instillation.

[0003] In some embodiments, the composition comprises 0.1% w / v brimonidine tartrate and 0.68% w / v timolol maleate. The composition may comprise 0.1% w / v brimonidine tartrate, 0.68% w / v timolol maleate, 0.1% w / v sodium chloride, 2.15% w / v disodium phosphate heptahydrate, 0.22% w / v monosodium phosphate monohydrate, and water. The composition may also comprise 0.1% w / v brimonidine tartrate, 0.68% w / v timolol maleate, 0.6% w / v boric acid, 0.38% sodium borate decahydrate, 0.5% w / v carboxymethylcellulose, 0.32% w / v sodium chloride, and water.

[0004] Depending on the composition, it may further contain at least one buffering agent selected from the group consisting of disodium phosphate heptahydrate and sodium borate decahydrate. Preferably, the composition has a pH of about 7, or pH 7.0. The composition may further contain one or both of sodium hydroxide and hydrochloric acid.

[0005] In some embodiments, administration of the present composition twice a day is at least as effective as administration of a second composition containing a fixed dose of 0.2% w / v brimonidine tartrate and 0.5% w / v timolol maleate twice a day. In some embodiments, administration of the present composition twice a day results in a reduced incidence of one or more adverse events compared to administration of a second composition containing a fixed dose of 0.2% w / v brimonidine tartrate and 0.68% w / v timolol maleate twice a day. The one or more adverse events can be selected from the group consisting of allergic conjunctivitis, conjunctival folliculosis, conjunctival hyperemia, ocular pruritus, ocular burning sensation, and ocular stinging. In certain embodiments, the composition does not contain a preservative. However, in some embodiments, the composition further contains benzalkonium chloride. Benzalkonium chloride may be present at a concentration of about 0.001% w / v to about 0.05% w / v.

[0006] One particular embodiment is a composition for reducing intraocular pressure, which essentially consists of 0.1% w / v brimonidine tartrate, 0.68% w / v timolol maleate, 0.1% w / v sodium chloride, 2.15% w / v disodium phosphate heptahydrate, 0.22% w / v monosodium phosphate monohydrate, and water.

[0007] Another particular embodiment is a composition for reducing intraocular pressure, which essentially consists of 0.1% w / v brimonidine tartrate, 0.68% w / v timolol maleate, 0.6% w / v boric acid, 0.38% sodium borate decahydrate, 0.5% w / v carboxymethylcellulose, 0.32% w / v sodium chloride, and water.

[0008] In another preferred embodiment, provided is a product comprising a packaging material and a pharmaceutical agent contained in the packaging material, the packaging material including a label indicating that the pharmaceutical agent can be used for reducing intraocular pressure, and the pharmaceutical agent being therapeutically effective for reducing intraocular pressure, the pharmaceutical agent including 0.1% brimonidine tartrate and 0.68% timolol maleate.

[0009] In some embodiments, the pharmaceutical agent includes 0.1% w / v brimonidine tartrate, 0.68% w / v timolol maleate, 0.1% w / v sodium chloride, 2.15% w / v disodium hydrogen phosphate heptahydrate, 0.22% w / v monosodium phosphate monohydrate, and water. In some embodiments, the pharmaceutical agent includes 0.1% w / v brimonidine tartrate, 0.68% w / v timolol maleate, 0.6% w / v boric acid, 0.38% sodium borate decahydrate, 0.5% w / v carboxymethylcellulose, 0.32% w / v sodium chloride, and water. The pharmaceutical agent may be provided in a unit-dose preservative-free formulation. The pharmaceutical agent may be provided in a multi-dose preservative-free formulation. The pharmaceutical agent may be provided in a multi-dose formulation preserved with one or more preservatives.

[0010] In yet another embodiment, provided is a method for treating glaucoma or ocular hypertension, the method including administering, in an effective amount, a single composition including about 0.1% w / v brimonidine tartrate and about 0.68% w / v timolol maleate.

[0011] In some embodiments, the composition is administered to the eye twice a day. In some embodiments, administration of the composition twice a day results in a reduced incidence of one or more adverse events compared to administration of a second single composition twice a day including 0.2% w / v brimonidine tartrate and 0.5% w / v timolol maleate. The one or more adverse events can be selected from the group consisting of allergic conjunctivitis, conjunctival folliculosis, conjunctival hyperemia, eye itching, eye burning, and eye stinging. BRIEF DESCRIPTION OF THE DRAWINGS

[0012]

FIG. 1A-C

FIG. 2A-C

[0013] Embodiments of the present invention relate to the topical ophthalmic use of a combination of brimonidine and timolol for the treatment of glaucoma, ocular hypertension, and reduction of intraocular pressure. Brimonidine and timolol are two drugs known to reduce intraocular pressure (''IOP''), but have been found to exhibit a synergistic effect when administered in combination. Among the benefits of such fixed combinations are enhanced therapeutic efficacy and enhanced therapeutic administration.

[0014] Brimonidine is an alpha - adrenergic receptor agonist represented by the following formula. The chemical name of brimonidine is 5 - bromo - 6-(2 - imidazolidinylideneamino)quinoxaline L - tartrate, and its structural formula is reproduced below. JPEG2025100564000001.jpg20170

[0015] Brimonidine inhibits the activation of adenylate cyclase through the activation of G - protein - coupled receptors. This reduces cAMP, and as a result, reduces aqueous humor production by the iris - ciliary body. Peripheral alpha2 - agonist activity results in vasoconstriction (in contrast to central alpha2 - agonist activity which reduces sympathetic tone as seen in clonidine pharmacotherapy). This vasoconstriction causes an acute decrease in aqueous humor flow. The increase in prostaglandin release due to alpha - adrenergic receptor stimulation resulting from long - term use of brimonidine increases the trabecular - meshwork - mediated uveoscleral outflow of aqueous humor, which, together with the aqueous humor - lowering effect of brimonidine, helps to reduce IOP in the treatment of open - angle glaucoma and ocular hypertension.

[0016] Brimonidine is commercially available as monotherapy at multiple concentrations (0.1%, 0.15%, 0.2% w / v brimonidine tartrate) and is sold by Allergan, Inc. as Alphagan® (or Iopidine® in Japan). Although brimonidine is preferably administered as the tartrate salt, other salt forms are possible. The free base can also be used.

[0017] Timolol is a non-selective beta-adrenergic receptor antagonist that reduces aqueous humor production through blockade of beta receptors in the ciliary epithelium. However, the exact pharmacological mechanism of the intraocular pressure-lowering effect of timolol has not been clearly established at present.

[0018] The chemical name of timolol is (S)-1-(tert-butylamino)-3-[(4-morpholin-4-yl-1,2,5-thiadiazol-3-yl)oxy]propan-2-ol and it has the following chemical structure. JPEG2025100564000002.jpg5092

[0019] Timolol is commercially available at multiple concentrations including 0.25% and 0.5% w / v timolol. One such brand is Timoptic®. Since timolol is preferably administered using the maleate salt, the above concentrations can also be expressed as 0.34% and 0.68% w / v timolol maleate. Of course, timolol can also be administered in other salt forms including the hemihydrate form. The free base can also be used.

[0020] In general usage, the concentration of timolol is often expressed as the composition as the free base without counterions. For example, a 0.5% w / v composition of timolol will typically be received as indicating a 0.5% w / v composition of timolol without counterions (i.e., in the free base form). This corresponds to 0.68% w / v timolol maleate which is the equivalent concentration.

[0021] In contrast, in common usage, the concentration of brimonidine may be expressed as the composition of brimonidine tartrate without explicitly mentioning the tartrate counterion. For example, a 0.2% w / v composition of brimonidine is typically understood to represent a 0.2% w / v composition of brimonidine tartrate and is not understood to be brimonidine without the counterion. The equivalent concentration of brimonidine without the counterion (i.e., in the free base form) is 0.132% w / v. Similarly, a 0.1% w / v composition of brimonidine tartrate is equivalent to 0.066% w / v of free base brimonidine.

[0022] In monotherapy, 0.2%, 0.15%, or 0.1% of brimonidine tartrate can be administered three times a day, while 0.68% of timolol maleate can be administered twice a day. In certain patients, such as those who are insufficient to appropriately control intraocular pressure in monotherapy, these two drugs can be used simultaneously in a combined manner. However, such a treatment regimen involves multiple difficulties, such as having to administer the first drug and then wait several minutes before administering the second drug. Also, since brimonidine needs to be administered three times a day while timolol only twice, patients may be further burdened with having to remember whether it is a dose of brimonidine alone or accidentally a dose with timolol. Studies have also shown that there may be an increased risk of adverse events as a result of such combination therapies.

[0023] Embodiments of the present invention relate to a fixed-dose composition comprising 0.1% w / v of brimonidine tartrate and 0.68% w / v of timolol maleate. In a fixed-dose composition, brimonidine and timolol are not administered separately but are administered in a single composition (e.g., in a single bottle). Such fixed-dose compositions provide many benefits as described herein.

[0024] Certain fixed-dose compositions of brimonidine and timolol, such as, without limitation, compositions containing 0.1% w / v of brimonidine tartrate and 0.68% w / v of timolol maleate, may have fewer side effects when administered compared to other drug compositions. For example, administration of the above composition may have fewer side effects compared to administration of monotherapy containing 0.2% w / v of brimonidine tartrate, or 0.15% w / v of brimonidine tartrate, or 0.1% w / v of brimonidine tartrate. Further, administration of the above composition may have fewer side effects compared to, for example, a fixed combination of 0.2% w / v of brimonidine tartrate and 0.68% w / v of timolol maleate.

[0025] Examples of reduced side effects that may be approved for the compositions disclosed herein include, but are not limited to, allergic conjunctivitis, conjunctival folliculosis, conjunctival hyperemia, ocular pruritus, ocular burning, and stinging. The compositions disclosed herein may also reduce the incidence of other side effects such as asthenia, blepharitis, corneal erosion, depression, epiphora, blepharitis, dry eye, ocular irritation, eye pain, eyelid edema, eyelid erythema, eyelid pruritus, foreign body sensation, headache, hypertension, dry mouth, drowsiness, punctate superficial keratitis, and visual impairment.

[0026] Preferably, the compositions disclosed herein are administered topically as a solution, particularly preferably an aqueous solution. In some embodiments, an emulsion is also possible. Preferably, the compositions disclosed herein are suitable for topical administration to the eye and ocular surface and are formulated for such administration.

[0027] When combined, certain embodiments can also include one or more viscosity enhancers. Examples of viscosity enhancers include viscosity enhancing polymers that can increase the viscosity of a particular composition and improve mucoadhesion. Without wishing to be bound by theory, the presence of a viscosity enhancer may extend the residence time of brimonidine and timolol on the corneal surface of the eye, thereby providing improved ocular absorption. Certain viscosity enhancing polymers include, among others, xanthan gum, sodium alginate, gellan gum, hyaluronic acid, Pemulen, poloxamer, carbomer, polycarbophil, chitosan, gelatin, pectin, and polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxpropylcellulose, and the like. Sodium carboxymethylcellulose is used as an example to increase the viscosity of the product in Composition B of Table 1.

[0028] Certain embodiments can also provide one or more additional preservatives. Any preservative suitable for topical ocular use and compatible with other compounds present in the composition can be incorporated into the embodiments disclosed herein. Such examples include, but are not limited to, benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, disodium edetate, sorbic acid, Purite® (stabilized chlorine dioxide), or other agents known to those skilled in the art. In a preferred embodiment, the preservative is benzalkonium chloride.

[0029] The possible concentration of benzalkonium chloride for use may be from about 0.001% w / v to about 0.05% w / v, more preferably from about 0.005% w / v to about 0.02% w / v. The appropriate concentration of thimerosal may be from about 0.001% to about 0.9% w / v. Chlorobutanol may be used at about 0.1% to about 0.5% w / v. Methylparaben may be used at about 0.1% to about 0.3% w / v. Propylparaben may be used at about 0.01% to about 0.2% w / v. Phenylethyl alcohol may be used at about 0.2% to about 0.5% w / v. Ethylenediaminetetraacetic acid (EDTA) may be used at about 0.005% to about 0.2% w / v. Sorbic acid may be used at about 0.05% to about 0.2% w / v. Purite® may be used at about 0.005% to about 0.02% w / v. For the other preservatives mentioned above, appropriate alternative concentrations can of course also be used.

[0030] In certain embodiments, the compositions disclosed herein can be formulated as a product that includes a pharmaceutical agent together with additional packaging material. Such packaging material preferably includes a label, which can be placed on the outside, inside, or as a separate booklet of the packaging material. This label can include information about the composition and the pharmaceutical agent contained therein, dosing information, patient safety information, regulatory information, physician / prescription information, and the like.

[0031] The embodiments disclosed in this specification can be provided, for example, in unit-dose configurations or in multi-dose configurations. Typically, a unit-dose configuration contains a single-dose composition in a container. Depending on the embodiment, this container may be in the form of non-reusable packaging, such as a capsule, an LDPE plastic vial, etc. Preferably, the unit-dose configuration contains a composition without the addition of a preservative. A multi-dose configuration may or may not contain a preservative, i.e., this configuration may contain a composition with or without a preservative, and typically, it can be dispensed at least twice, preferably multiple times, in a certain dose from a container containing the multi-dose composition. Containers that can be used for such multi-dose configurations can include typical eye-drop bottles or other types of bottles. In a multi-dose preservative-free configuration, it is preferable to provide the container with certain mechanisms that are thought to prevent or delay microbial growth in order to prevent the risk of eye infections and the potential degradation of the composition remaining in the container. Such mechanisms can include applying an antibacterial coating to the container, as well as container dispensing and hole configurations (e.g., filters, one-way holes, etc.) that prevent microbial intrusion into the container.

Example

[0032] Example 1 Table 1 shows two embodiments of a composition of a fixed-dose combination containing 0.1% brimonidine tartrate and 0.5% timolol free base (i.e., 0.68% timolol maleate). These compositions are preferably buffered, isotonic, sterile, and preservative-free ophthalmic solutions for topical administration. As container closure systems used for delivering these compositions, unit-dose LDPE plastic vials or improved multi-dose eye-drop bottles with self-preserving properties that prevent the intrusion of impurities during use are possible. Of course, compositions containing preservatives are also possible.

[0033] Table 1. Examples of Fixed-Dose Combinations of Brimonidine and Timolol JPEG2025100564000003.jpg78158

[0034] Compared with commercially available brimonidine and timolol monotherapy products, the compositions of the preservative-free embodiments described in Table 1 provide better safety profiles for chronic use of the products in certain patients, such as those with an ocular surface sensitive to damage or irritation that may be caused by certain preservatives.

[0035] Of course, the above embodiments are not limited to preservative-free compositions. Any preservative suitable for topical ocular use can be incorporated into the brimonidine / timolol combination product, and examples of such preservatives include, but are not limited to, benzalkonium chloride and the other preservatives mentioned above. For example, suitable concentrations of benzalkonium chloride can be from about 0.005% to about 0.02% w / v, such as 0.005% w / v, 0.01% w / v, or 0.02% w / v. Suitable concentrations of thimerosal can be from about 0.001% to about 0.9% w / v. Chlorobutanol may be used at about 0.1% to about 0.5% w / v. Methylparaben may be used at about 0.1% to about 0.3% w / v. Propylparaben may be used at about 0.01% to about 0.2% w / v. Phenylethyl alcohol may be used at about 0.2% to about 0.5% w / v. Ethylenediaminetetraacetic acid (EDTA) may be used at about 0.005% to about 0.2% w / v. Sorbic acid may be used at about 0.05% to about 0.2% w / v.

[0036] Example 2 Pharmacokinetic ("PK") experiments were conducted to evaluate the ocular and systemic absorption of brimonidine and timolol in rabbits after topical administration of the two compositions presented in Table 1.

[0037] Table 2 shows the experimental design of the rabbit experiment using Compositions A and B in Table 1. Rabbits were randomly assigned to groups based on body weight, and single bilateral topical eye drops of the test composition (Composition A or B) and the comparators (Alphagan® and Timoptic®) were administered. Specifically, each group consisted of 12 female rabbits, and 2 animals (a total of 4 eyes) were tested at each time point. The dosing consisted of single bilateral topical dosing using a dosing volume of 35 μL. Samples were collected at 15, 30, 60, 120, 240, and 480 minutes after dosing and quantitatively analyzed to determine the tissue and plasma concentrations of brimonidine and timolol.

[0038] Table 2. Pharmacokinetic study of 0.1% brimonidine tartrate / 0.5% timolol combination composition JPEG2025100564000004.jpg66155a: Set a 5-minute interval between the administrations of the two eye drops

[0039] When the 0.1% brimonidine tartrate / 0.5% timolol combination composition was administered, an increase in ocular timolol exposure was observed compared to 0.5% timolol monotherapy. This finding is not obvious to those skilled in the art.

[0040] The results of the rabbit PK study are summarized in Tables 3 and 4, as well as in Figures 1 and 2. Tables 3 and 1 show the amount of brimonidine found in rabbit aqueous humor, iris-ciliary body, and plasma. Note that the results of the sequential dosing regimen are not reproduced in Figure 1. The iris-ciliary body is a target tissue for both brimonidine and timolol due to their IOP-lowering effects, while the aqueous humor is the fluid in which the iris-ciliary body is immersed. As a result, the drug concentration in the aqueous humor often has a high correlation with the drug concentration in the parenchymal tissue of the iris-ciliary body. Due to nasolacrimal drainage, topically applied eye drops result in drug exposure in the systemic circulation, and the exposure range is evaluated by the drug concentration in the plasma. This concentration often correlates with the systemic side effects associated with the drug.

[0041] In the above description, "C" max"Cmax" represents the peak drug concentration reached during the experiment. "AUC" represents the area under the curve of the drug concentration-time curve.

[0042] Figure 1B shows that in the iris-ciliary body, both Composition A and Composition B achieved higher Cmax and AUC values of brimonidine than the administration of 0.1% brimonidine tartrate alone. This is a promising result because the iris-ciliary body is the target tissue for reducing IOP. max

[0043] Figures 1A and 1C show the brimonidine concentrations in aqueous humor and plasma respectively. In these figures, both Composition A and Composition B resulted in lower Cmax and AUC values than 0.1% brimonidine tartrate alone. max

[0044] Table 3 summarizes the pharmacokinetic parameters obtained from the experiments shown in Figures 1A - 1C.

[0045] In Figures 2A and 2B, both Composition A and Composition B showed higher ocular timolol exposure in aqueous humor and iris-ciliary body than the administration of 0.5% timolol alone. Next, in Figure 2C, the plasma concentrations of Composition A and Composition B showed decreased concentrations compared to the administration of 0.5% timolol alone. These decreased plasma concentrations are favorable for the purpose of reducing the systemic exposure of timolol, which may have cardiovascular side effects.

[0046] Table 4 summarizes the pharmacokinetic parameters obtained from the experiments shown in Figures 2A - 2C. Table 3. Brimonidine PK Characteristics JPEG2025100564000005.jpg88160a: Set a 5-minute interval between the administrations of the two eye drops Cmax max Values are comparable between groups by one-way analysis of variance (p > 0.05)

[0047] Table 4. Timolol PK Characteristics ​​JPEG2025100564000006.jpg83160a: Provide a 5-minute interval between the administrations of two kinds of eye drops C max The values are comparable between groups (p > 0.05 in one-way analysis of variance)

[0048] Unless otherwise indicated, all numbers representing properties such as amounts of components, molecular weights, and reaction conditions used in this specification and the claims are to be modified in all cases by the term "about". Accordingly, unless otherwise indicated, the numerical parameters set forth in this specification and the appended claims are approximations that may vary depending upon the desired properties sought to be obtained. At a minimum, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits recited and by applying ordinary rounding techniques.

[0049] The terms "a", "an", "the" (the, said) and similar descriptions used in the context of describing the present invention (particularly in the context of the following claims) are to be construed to include both the singular and the plural unless otherwise indicated herein or clearly contradicted from the context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted from the context. The use of any example, or exemplary language (e.g., "such as") provided herein is for the purpose of making the present invention more understandable only and does not limit the scope of any claim. There should be no element not claimed in the claims that is to be regarded as essential to the practice of the invention indicated by the language in the specification.

[0050] The grouping of alternative elements or embodiments disclosed herein is not to be regarded as a limitation. Each group member may be referred to and claimed individually, or in any combination with other members of the group or other components found herein. One or more members of a group may be included in or deleted from a group for reasons of brevity and / or patentability. Whatever such inclusion or deletion may occur, the specification is considered to contain the group as so modified and thus to satisfy the written description of all the Markush groups used in the appended claims.

[0051] Certain embodiments are described herein, including those that are known to the inventors to be the optimal modes for carrying out the invention. Of course, modifications of those described embodiments will be apparent to those skilled in the art upon reading the above description. The inventors expect those skilled in the art to adopt such modifications as appropriate, and the inventors intend that the invention be practiced in ways other than those specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Moreover, any combination of those components in all possible variations thereof is contemplated unless otherwise specifically shown herein or clearly contradicted from the context.

[0052] Of course, the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. That is, by way of example and not limitation, alternative embodiments may be utilized in accordance with the teachings of this specification. Accordingly, the claims are not limited to the embodiments as shown and described.

Claims

1. A composition comprising about 0.1% w / v brimonidine tartrate and about 0.68% w / v timolol maleate.

2. The composition according to claim 1, wherein the composition comprises 0.1% w / v brimonidine tartrate and 0.68% w / v timolol maleate.

3. The composition according to claim 2, wherein the composition comprises 0.1% w / v brimonidine tartrate, 0.68% w / v timolol maleate, 0.1% w / v sodium chloride, 2.15% w / v disodium phosphate heptahydrate, 0.22% w / v monosodium phosphate monohydrate, and water.

4. The composition according to claim 2, wherein the composition comprises 0.1% w / v brimonidine tartrate, 0.68% w / v timolol maleate, 0.6% w / v boric acid, 0.38% sodium borate decahydrate, 0.5% w / v carboxymethylcellulose, 0.32% w / v sodium chloride, and water.

5. The composition according to claim 1, further comprising at least one buffering agent selected from the group consisting of disodium phosphate heptahydrate and sodium borate decahydrate.

6. The composition according to any one of the preceding claims, wherein the composition has a pH of about 7.

7. The composition according to claim 6, wherein the composition has a pH of 7.

0.

8. The composition according to any one of claims 1 to 7, further comprising one or both of sodium hydroxide and hydrochloric acid.

9. The composition according to any one of claims 1 to 8, wherein administration of the composition twice a day is as effective as administration of a second composition twice a day containing a fixed dose of at least 0.2% w / v brimonidine tartrate and 0.5% w / v timolol maleate.

10. The composition according to any one of claims 1 to 9, wherein administration of the composition twice a day results in a reduced incidence of one or more adverse events compared to administration of a second composition twice a day containing a fixed dose of 0.2% w / v brimonidine tartrate and 0.68% w / v timolol maleate.

11. The composition according to claim 10, wherein the one or more adverse events are selected from the group consisting of allergic conjunctivitis, conjunctival folliculosis, conjunctival congestion, eye itching, eye burning sensation, and eye stinging pain.

12. The composition according to any one of claims 1 to 11, which does not contain a preservative.

13. The composition according to any one of claims 1 to 11, which further contains benzalkonium chloride.

14. The composition according to claim 13, wherein the benzalkonium chloride is present at a concentration of about 0.001% w / v to about 0.05% w / v.

15. The composition according to any one of claims 1 to 14, which is configured for topical eye drops.

16. The composition according to any one of claims 1 to 15, which is for the treatment of glaucoma and ocular hypertension.

17. A composition for reducing intraocular pressure, which essentially consists of 0.1% w / v of brimonidine tartrate, 0.68% w / v of timolol maleate, 0.1% w / v of sodium chloride, 2.15% w / v of disodium hydrogen phosphate heptahydrate, 0.22% w / v of monosodium phosphate monohydrate, and water.

18. A composition for reducing intraocular pressure, which essentially consists of 0.1% w / v of brimonidine tartrate, 0.68% w / v of timolol maleate, 0.6% w / v of boric acid, 0.38% of sodium borate decahydrate, 0.5% w / v of carboxymethyl cellulose, 0.32% w / v of sodium chloride, and water.

19. A product comprising a packaging material and a pharmaceutical agent contained in the packaging material, wherein the packaging material includes a label indicating that the pharmaceutical agent can be used for reducing intraocular pressure, and the pharmaceutical agent is therapeutically effective for reducing intraocular pressure, and the pharmaceutical agent contains 0.1% of brimonidine tartrate and 0.68% of timolol maleate.

20. The product according to claim 19, wherein the pharmaceutical agent contains 0.1% w / v of brimonidine tartrate, 0.68% w / v of timolol maleate, 0.1% w / v of sodium chloride, 2.15% w / v of disodium hydrogen phosphate heptahydrate, 0.22% w / v of monosodium phosphate monohydrate, and water.

21. The pharmaceutical agent according to claim 19, comprising 0.1% w / v brimonidine tartrate, 0.68% w / v timolol maleate, 0.6% w / v boric acid, 0.38% sodium borate decahydrate, 0.5% w / v carboxymethylcellulose, 0.32% w / v sodium chloride, and water.

22. The product according to any one of claims 19 to 21, wherein the pharmaceutical agent is provided in a configuration that does not contain a preservative in a unit dose.

23. The product according to any one of claims 19 to 21, wherein the pharmaceutical agent is provided in a configuration that does not contain a preservative in a multiple dose.

24. The product according to any one of claims 19 to 21, wherein the pharmaceutical agent is provided in a multiple dose configuration preserved with one or more preservatives.

25. A method for treating glaucoma or ocular hypertension, the method comprising administering, in an effective amount, a single composition comprising about 0.1% w / v brimonidine tartrate and about 0.68% w / v timolol maleate.

26. The method according to claim 25, wherein the composition is administered to the eye twice a day.

27. The method according to claim 26, wherein the twice-daily administration of the composition results in a reduced incidence of one or more adverse events compared to the twice-daily administration of a second single composition comprising 0.2% w / v brimonidine tartrate and 0.5% w / v timolol maleate.

28. The one or more adverse events according to claim 27, selected from the group consisting of allergic conjunctivitis, conjunctival folliculosis, conjunctival hyperemia, ocular pruritus, ocular burning sensation, and ocular stinging pain.

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