# Patent

## Title
Method for treating ocular hypertension and glaucoma

## Abstract

Provided is a method for treating ocular hypertension and glaucoma with reduced side effects such as keratoconjunctive disorders and macular edema, which comprises administering an ophthalmic composition comprising latanoprost as an active ingredient thereof to a subject in need of said treatment, wherein the ophthalmic composition contains substantially no benzalkonium chloride.

## Background
RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application Ser. Nos. 60/420,776 filed Oct. 24, 2002 and 60/421,044 filed Oct. 25, 2002.


TECHNICAL FIELD
The present invention relates to a method for treating ocular hypertension and glaucoma with reduced side effects, which comprises administering an ophthalmic composition comprising latanoprost as an active ingredient thereof, which contains substantially no benzalkonium chloride.
BACKGROUND ART
Preservatives used in ophthalmic composition are required to exhibit sufficient antimicrobial effect on bacteria and fungi as well as high degree of safety such that inducing no or small affection on eye tissues such as corneal epithelium. In addition to the original purposes as above, the preservatives themselves are required to be stable. Further, the preservatives are required to homogenize and stabilize the composition by interacting with the ingredients, for example, by homogeneously dispersing or dissolving the ingredients into the vehicle or base. Benzalkonium chloride is a preservative most commonly used in commercially available ophthalmic solution.
However, preservatives are known as the major etiology of keratoconjunctive disorders, and for safety purpose, it is preferred that the concentration of a preservative such as benzalkonium chloride is below 0.01%. According to recent reports, preservatives contained in ophthalmic solution cause blood-aqueous barrier disruption and macular edema, especially cystoid macular edema (hereinafter referred to as “CME”) (The 105th General Assembly of Japan Ophthalmological Society, P.112, OSN Supersite, Top Stories, 1997 Oct. 02, the contents are herein incorporated by reference).
Xalatan® ophthalmic solution, which has been marketed as a drug for treating ocular hypertension and glaucoma, contains latanoprost as an active ingredient thereof. Xalatan® ophthalmic solution contains benzalkonium chloride as a preservative at a concentration of 0.02% (package insert of Xalatan®), and side effects such as keratoconjunctive disorders and CME caused by such high concentration of the preservative have been the problem.
However, since latanoprost is highly fat-soluble, it has been believed to be difficult to prepare homogeneous and stable latanoprost ophthalmic composition without benzalkonium chloride. To the present, latanoprost ophthalmic composition containing no or less than 0.02% of benzalkonium chloride has not been provided as a commercially available product.
SUMMARY OF THE INVENTION
The present invention relates to a method for treating ocular hypertension and glaucoma, which comprises administering an ophthalmic composition comprising latanoprost as an active ingredient thereof to a subject in need of said treatment, wherein the ophthalmic composition contains substantially no benzalkonium chloride.
Especially, the present invention relates to a method for treating ocular hypertension and glaucoma, which comprises administering an ophthalmic composition comprising latanoprost as an active ingredient thereof to a subject who has ocular hypertension and glaucoma and is in need of treatment or prevention of keratoconjunctive disorders or macular edema, wherein the ophthalmic composition contains substantially no benzalkonium chloride.
The present invention also relates to an ophthalmic composition for treating ocular hypertension and glaucoma comprising latanoprost as an active ingredient thereof, which contains substantially no benzalkonium chloride.
Further, the present invention relates to a use of latanoprost for manufacturing an ophthalmic composition for treating ocular hypertension and glaucoma, which contains substantially no benzalkonium chloride.
The phrase of “the ophthalmic composition contains substantially no benzalkonium chloride” used herein means that the composition contains no benzalkonium chloride, or the composition contains benzalkonium chloride at a concentration that if the amount of benzalkonium chloride in the commercially available Xalatan® ophthalmic solution is reduced below said concentration, homogenous and/or stable solution is difficult to be prepared. In the present invention, the ophthalmic composition may contain Benzalkonium chloride at a concentration of less than 0.02%, preferably 0.01% or less, more preferably 0.005% or less.
The term “treatment” or “treating” used herein includes any means of control such as prevention, care, relief of symptoms, attenuation of symptoms and arrest of progression.


DETAILED DESCRIPTION OF THE INVENTION
The ophthalmic composition of the present invention may be formulated as any dosage form used in the ophthalmic field. For example, the ophthalmic composition may be in liquid form such as solution, emulsion and suspension or semisolid form such as gel and eye ointment. Ophthalmic solution including emulsion and suspension as well as solution is preferably used. The ingredients other than latanoprost may not be particularly limited as far as latanoprost is homogeneously and stably dispersed or dissolved in the composition. Ophthalmic composition of the present invention may be manufactured according to any of conventional methods.
In case of the composition is an ophthalmic solution, the composition may further contain a dissolving agent. The dissolving agents used in the present invention may be any of conventionally used agents as far as it helps to disperse or dissolve latanoprost homogeneously and stably in an aqueous vehicle containing substantially no benzalkonium chloride. Examples of the dissolving agents may include polyoxyethylenesorbitan higher aliphatic acid monoester such as polysorbate 80, EDTA, boric acid, chlorhexidine gluconate, sodium persulfate, glycerol, concentrated glycerol, polyoxylated caster oil such as polyoxyethylene hydrogenated castor oil 40 and polyoxyethylene hydrogenated castor oil 60, polyoxyl stearate, macrogol, propyleneglycol, povidone, lower alcohol such as ethanol and chlorobutanol. Polysorbate 80 and EDTA are especially preferred. The dissolving agent may be used solely or in combination with one or more other dissolving agents.
The ophthalmic composition of the present invention may further contain additives other than the above-listed dissolving agents. According to the present invention, the additives may be any of those conventionally used in the ophthalmic field. Examples of the additives may include osmotic adjusting agents such as sodium chloride, potassium chloride, calcium chloride, sodium bicarbonate, sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, borax, sodium hydroxide, hydrochloric acid, isosorbitol, propylene glycol, mannitol, sucrose and glucose; buffering agents such as sodium monohydrogen phosphate and sodium dihydrogen phosphate; thickeners such as saccharides (e.g. lactose and maltose), hyaluronic acids or salt thereof (e.g. sodium hyaluronate and potassium hyaluronate), mucopolysaccharides (e.g. chondroitin sulfate), sodium polyacrylate, carboxyvinyl polymer and crosslinked polyacrylate.
When the composition is an eye ointment, the composition may contain ordinarily used eye ointment bases in addition to the above additives. Examples of eye ointment bases may include oil base such as Vaseline, liquid paraffin, polyethylene, Selen 50, Plastibase, macrogol and a combination thereof; emulsion base in which oil phase and aqueous phase have been emulsified with a surface active agent or the like; and water soluble base such as hydroxypropylmethylcellulose, carboxypropylcellulose and polyethylene glycol.
According to the present invention, it is easy to prepare homogenous and stable latanoprost ophthalmic composition containing less than 0.02% of benzalkonium by admixing a dissolving agent. The ophthalmic composition of the present invention may be prepared as a sterile unit dose type formulation for single use. Furthermore, since the ophthalmic composition of the present invention causes significantly fewer side effects such as keratoconjunctive disorders and CME than commercially available Xalatan® ophthalmic solution, the method of the present invention provides more effective treatment to a subject suffering from keratoconjunctive disorder and/or macular edema such as CME.
The concentration of latanoprost in the composition and dosing frequency may vary according to the type of the subject such as species, age, sex, body weight and general health, symptoms to be treated, desired therapeutic effects, administration route, period of treatment and the like. For example, an ophthalmic solution containing latanoprost at a concentration of 0.00001 to 1%, preferably 0.0001 to 0.1%, more preferably 0.001 to 0.01% may be instilled 1 to 4 times, preferably 1 to 3 times, more preferably 1 to 2 times a day.
In the present invention, the composition may contain pharmaceutically active ingredients other than latanoprost as far as they are not contrary to the objects of the present invention. Examples of the pharmaceutically active ingredients may include parasympathomimetic agents such as pilocarpine and carbachol; cholinesterase inhibitors such as physostigmine salicylate, distigmine bromide and echothiopate iodide; sympathomimetic agents such as epinephrine, dipivalylepinephrine, clonidine, p-aminoclonidine and brimonidine; β-adrenergic blockers such as betaxolol, levobunolol, timolol and carteolol; prostaglandin compounds such as isopropyl unoprostone, travoprost and bimatoprost; tropicamide and the like. Among these pharmaceutically active agents, timolol is especially preferable. In the preparation that contains two or more active ingredients, the amount of each ingredient may be determined appropriately according to the therapeutic effects and safety of each ingredient.
The present invention will be described in more detail with reference to the following examples, which is not intended to limit the scope of the present invention.
EXAMPLE
Latanoprost was mixed in various additives at the amount shown in table 1 below respectively to prepare 0.005% latanoprost ophthalmic solution. 10 mL of each of the solution was agitated for seven hours and then stood still for 30 minutes. After that, the concentration of the latanoprost in the solutions was measured by HPLC and determined by internal standard method with one point calibration curve.




  
    Concentration
    ⁢
    
      
    
    ⁢
    of
    ⁢
    
      
    
    ⁢
    
      latanoprost
      ⁢
      
        
          
        
        ⁢
        
          
        
      
      (
      
        mg
        ⁢
        
          /
        
        ⁢
        mL
      
      )
    
  
  =
  
    0.004
    ×
    
      W
      S
    
    ×
    
      
        Q
        T
      
      
        Q
        S
      
    
  




    
    
        Ws: The amount of latanoprost in the standard preparation (mg)
        Qs: Peak area ratio of latanoprost in the standard preparation to the internal standard
        Qt: Peak area ratio of latanoprost in the test preparation to the internal standard
    
    


The results are shown in Table 1 below.







TABLE 1







Concentration of latanoprost in the various latanoprost ophthalmic solution










Test
Amount of additives (%)
Conc.*3
















No.
BAC*1
P80*2
EDTA
NaH2PO4—H2O
Na2HPO4
NaCl
(mg/mL)
Homogeneity*4


















1
—
—
—
0.46
0.47
0.41
0.04415
88.3


2
—
0.2
—
0.46
0.47
0.41
0.04998
100.0


3
0.01
—
—
0.46
0.47
0.41
0.04863
97.3


4
0.01
0.2
—
0.46
0.47
0.41
0.04994
99.9


5
0.01
0.2
0.05
0.46
0.47
0.41
0.04993
99.9





*1BAC: Benzalkonium chloride


*2P80: polysorbate 80


*3concentration of latanoprost


*4ratio (%) of latanoprost in the solutions 30 minutes after the agitation for seven hours to initially used latanoprost






As is shown in Test Nos. 1 and 2, the homogeneity of latanoprost in the ophthalmic solution without benzalkonium chloride was improved by admixing polysorbate 80 (88.3% to 100.0%).
As is shown in Test Nos. 3–5 of Table 1, the homogeneity of latanoprost in the ophthalmic solution with 0.01% of benzalkonium chloride was improved by admixing polysorbate 80 or, polysorbate 80 and EDTA (97.3% to 99.9%).
These results suggested that the homogeneity and stability of latanoprost ophthalmic solution were improved by admixing a dissolving agent.

## Claims

1. A method for treatment of ocular hypertension and glaucoma, which comprises administering an ophthalmic composition comprising latanoprost, polysorbate 80 and EDTA, wherein latanoprost is the sole active ingredient of the composition, to a subject in need of said treatment, wherein the ophthalmic composition contains 0.01% or less of benzalkonium chloride.

2. The method as described in claim 1, wherein the ophthalmic composition is formulated as a single-unit dose preparation.

3. The method as described in claim 1, wherein the ophthalmic composition is an ophthalmic solution.

4. A method for treating ocular hypertension and glaucoma, which comprises administering an ophthalmic composition comprising latanoprost, polysorbate 80 and EDTA, wherein latanoprost is the sole active ingredient of the composition, to a subject who has ocular hypertension and glaucoma and is in need of treatment or prevention of keratoconjunctive disorders or macular edema, wherein the ophthalmic composition contains 0.01% or less of benzalkonium chloride.

5. The method as described in claim 4, wherein the ophthalmic composition is formulated as a single-unit dose preparation.

6. The method as described in claim 4, wherein the ophthalmic composition is an ophthalmic solution.

7. The method as described in claim 1, wherein the concentration of benzalkonium chloride is 0.005% or less.

8. The method as described in claim 4, wherein the concentration of benzalkonium chloride is 0.005% or less.