Abstract:
An ophthalmic solution comprising a polyethoxylated glyceride in the range of 0.001 to about 10 percent by weight and a buffer agent. These solutions impart surprising comfort and wearability to contact lenses. At the same time the solutions provide good preservative capacity and do not increase protein deposit.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application is continuation of and claims priority from U.S. patent application Ser. No. 12/693,878, filed Jan. 26, 2010 which is a continuation U.S. patent application Ser. No. 10/842,162, filed May 10, 2004, now U.S. Pat. No. 7,678,836 which is a continuation of U.S. patent application Ser. No. 09/706,338 filed Nov. 4, 2000 which claims priority from U.S. Provisional application Ser. No. 60/163,455 filed Nov. 4, 1999. The contents of which are incorporated in their entirety by reference. 
     
    
     BACKGROUND 
       [0002]    The present invention relates to novel ophthalmic solutions that contain a ethoxylated glyceride as an additive to improve the wettability and to decrease the degree of protein and polymeric preservative binding to contact lens surfaces. These compositions may also comprise other agents in contact lens and ophthalmic solutions such as buffers, tonicity agents, wetting agents, enzymes, hydrogen peroxide, demulcents, thickeners, sequestering agents (chelating agents), surface active agents and preservative agents. The ethoxylated glycerides are particularly useful in contact lens treatment solutions, contact lens wetting solutions, solutions used to store contact lenses and solutions used to clean or rinse contact lenses. It has been found that surprisingly the addition of ethoxylated glycerides improve the comfort of lenses treated with such solution and that this increased comfort is surprisingly long-lasting in its effect. The ethoxylated glycerides maybe mono-, di- or triglycerides; 
     
    
     DETAILED DESCRIPTION 
       [0003]    The solutions of the present invention are made by one of two methods. First the ethoxylated glyceride may be melted and added to an aqueous solution which includes the other agents to be used in the desired formulation, or the additional agents may be added prior to the addition of the melted ethoxylated glyceride. Second, the ethoxylated glyceride may be dissolved in an alcohol base and this liquid mixture, added to the aqueous base. Ethoxylated glycerides are commercially available from numerous commercial sources and include Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40), polyoxyl 60 hydrogenated castor oil (Cremophor RH 60), PEG-30 Castor Oil (Incrocas 30), PEG-35 Castor Oil (Cremophor EL, Incrocas 35), or PEG-40 Castor Oil (Cremophor EL, Incrocas), Cremophor EL®, Emulphor EL®, glycerol polyethyleneglycol riciinoleate, gycerol polyethyleneglycol oxystearate, polyethoxylated hydrogenated castor oil, or polyethoxylated vegetable oil. The ethoxylated glycerides useful in the present invention may include surfactants sold as PEG-6 Caprylic/Capric Glycerides PEG-8 Caprylic/Capric Glycerides; PEG-2 Castor Oil; PEG-3 Castor Oil; PEG-4 Castor Oil; PEG-5 Castor Oil; PEG-8 Castor Oil; PEG-9 Castor Oil; PEG-10 Castor Oil; PEG-11 Castor Oil; PEG-15 Castor Oil; PEG-20 Castor Oil; PEG-25 Castor Oil; PEG-30 Castor Oil; PEG-33 Castor Oil; PEG-35 Castor Oil; PEG-36 Castor Oil; PEG-40 Castor Oil; PEG-50 Castor Oil; PEG-54 Castor Oil; PEG-55 Castor Oil; PEG-60 Castor Oil; PEG-100 Castor Oil; PEG-200 Castor Oil; PEG-18 Castor Oil Dioleate; PEG-60 Corn Glycerides; PEG-20 Evening Primrose Glycerides; 
         [0004]    PEG-60 Evening Primrose Glycerides; PEG-7 Glyceryl Cocoate; PEG-30 Glyceryl Cocoate; PEG-78 Glyceryl Cocoate; PEG-80 Glyceryl Cocoate; PEG-12 Glyceryl Dioleate; PEG-15 Glyceryl Isostearate; PEG-20 Glyceryl Isostearate; PEG-30 Glyceryl Isostearate; PEG-60 Glyceryl Isostearate; PEG-12 Glyceryl Laurate; PEG-20 Glyceryl Laurate; PEG-23 Glyceryl Laurate; PEG-30 Glyceryl Laurate; PEG-10 Glyceryl Oleate; PEG-15 Glyceryl Oleate; PEG-30 Glyceryl Oleate; PEG-20 Glyceryl Ricinoleate; PEG-5 Glyceryl Sesquioleate; PEG-S Glyceryl Stearate; PEG-10 Glyceryl Stearate; PEG-25 Glyceryl Stearate; PEG-30 Glyceryl Stearate; PEG-120 Glyceryl Stearate; PEG-200 Glyceryl Stearate; PEG-28 Glyceryl Tallowate; PEG-80 Glyceryl Tallowate; PEG-200 Glyceryl Tallowate; PEG-S Glyceryl Triisostearate; PEG-5 Hydrogenated Castor Oil; PEG-7 Hydrogenated Castor Oil; PEG-16 Hydrogenated Castor Oil; PEG-20 Hydrogenated Castor Oil; PEG-25 Hydrogenate Castor Oil; PEG-30 Hydrogenate Castor Oil; PEG-35 Hydrogenate Castor Oil; PEG-40 Hydrogenate Castor Oil; PEG-45 Hydrogenate Castor Oil; PEG-50 Hydrogenate Castor Oil; PEG-54 Hydrogenate Castor Oil; PEG-55 Hydrogenate Castor Oil; PEG-60 Hydrogenate Castor Oil; PEG-80 Hydrogenate Castor Oil; PEG-100 Hydrogenate Castor Oil; PEG-200 Hydrogenate Castor Oil; PEG-40 Hydrogenated Castor Oil PCA Isosterate; PEG-5 Hydrogenated Corn Glycerides; and PEG-8 Hydrogenated Fish Glycerides; which are all available from known commercial sources 
         [0005]    The solutions of the present invention may contain other additives including but not limited to buffers, tonicity agents, demulcents, wetting agents, preservatives, sequestering agents (chelating agents), surface active agents, and enzymes. 
         [0006]    Other aspects of the claimed solutions include adding to the solution from 0.001 to 1 weight percent chelating agent (preferably disodium EDTA) and/or additional microbicide, (preferably 0.00001 to 0.1 or 0.00001 to 0.01) weight percent polyhexamethylene biquanide (PHMBO, N-alkyl-2-pyrrolidone, chlorhexidine, polyquatemium-1, hexetidine, bronopol, alexidine, low concentrations of hydrogen peroxide, and ophthalmologically acceptable salts thereof 
         [0007]    Ophthalmologically acceptable chelating agents useful in the present invention include amino carboxylic acid compounds or water-soluble salts thereof, including ethylenediaminetetraacetic acid, nitrilotriacetic acid, diethylenetriamine pentaacetic acid, hydroxyethylethylenediaminetriacetic acid, 1,2-diaminocyclohexanetetraacetic acid, ethylene glycol his (beta-aminoethyl ether) in N,N,N′,N′ tetraacetic acid (EGTA), aminodiacetic acid and hydroxyethylamino diacetic acid. These acids can be used in the form of their water soluble salts, particularly their alkali metal salts. Especially preferred chelating agents are the di-, tri- and tetra-sodium salts of ethylenediaminetetraacetic acid (EDTA), most preferably disodium EDTA (Disodium Edetate). 
         [0008]    Other chelating agents such as citrates and polyphosphates can also be used in the present invention. The citrates which can be used in the present invention include citric acid and its mono-, di-, and tri-alkaline metal salts. The polyphosphates which can be used include pyrophosphates, triphosphates, tetraphosphates, trimetaphosphates, tetrametaphosphates, as well as more highly condensed phosphates in the form of the neutral or acidic alkali metal salts such as the sodium and potassium salts as well as the ammonium salt. 
         [0009]    The pH of the solutions should be adjusted to be compatible with the eye and the contact lens, such as between 6.0 to 8.0, preferably between 6.8 to 7.8 or between 7.0 to 7.6. Significant deviations from neutral (pH 7.3) will cause changes in the physical parameters (i.e. diameter) in some contact lenses. Low pH (pH less than 5.5) can cause burning and stinging of the eyes, while very low or very high pH (less than 3.0 or greater than 10) can cause ocular damage. 
         [0010]    The additional preservatives employed in the present invention are known, such as polyhexamethylene biguanide, N-alkyl-2-pyrrolidone, chlorhexidine, polyhexamethylenebiguanide, alexidine, polyquatemium-1, hexetidine, bronopol and a very low concentration of hydrogen peroxide, e.g., 30 to 200 rpm. 
         [0011]    The solutions of the invention are compatible with both rigid gas permeable and hydrophilic contact lenses during storage, cleaning, wetting, soaking, rinsing and disinfection. 
         [0012]    A typical aqueous solution of the present invention may contain additional ingredients which would not affect the basic and novel characteristics of the active ingredients described earlier, such as tonicity agents, surfactants and viscosity inducing agents, which may aid in either the lens cleaning or in providing lubrication to the eye. Suitable tonicity agents include sodium chloride, potassium chloride, glycerol or mixtures thereof. The tonicity of the solution is typically adjusted to approximately 240-310 milliosmoles per kilogram solution (mOsm/kg) to render the solution compatible with ocular tissue and with hydrophilic contact lenses. In one embodiment, the solution contains 0.01 to 0.5 weight percent sodium chloride. 
         [0013]    Suitable viscosity inducing agents can include lecithin or the cellulose derivatives such as hydroxymethylcellulose, hydroxypropylcellulose and methylcellulose in amounts similar to those for surfactants, above. 
       EXAMPLE 1 
       [0014]    Hydrophilic contact lenses were placed flat onto glass slides and rinsed with water to remove any debris. These slides were placed in a petri dish and covered with a few drops of each of the test solutions previously prepared in either water, an aqueous isotonic sodium chloride solution, or an aqueous phosphate buffered solution made isotonic with sodium chloride and adjusted to pH 7.3. Each petri plate was covered and placed in a refrigerator overnight. The following day, the slides were removed and allowed to equilibrate to room temperature. The lenses were rinsed with water and the excess water was removed. One 5 uL drop of mineral oil stained with Oil Red 0 was placed onto one lens for each solution. After ten minutes, the lenses were observed for the ability of the oil drop to spread. 
         [0000]    
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                 Oil 
                 Water 
               
               
                 Additive 
                 Solution Matrix 
                 Dispersibility 
                 Dispersibility 
               
               
                   
               
             
             
               
                 1% polyoxyl 40 
                 water 
                 4 
                 5 
               
               
                 hydrogenated castor oil 
                   
                   
                   
               
               
                 (Cremophor RH 40) 
                   
                   
                   
               
               
                 1% polyoxyl 40 
                 buffer 
                 5 
                 5 
               
               
                 hydrogenated castor oil 
                 water 
                   
                   
               
               
                 (Cremophor RH 40) 
                   
                   
                   
               
               
                 1% polyoxyl 40 
                 sodium choride 
                 2 
                 5 
               
               
                 hydrogenated castor oil 
                 water 
                   
                   
               
               
                 (Crernophor RH 40) 
                   
                   
                   
               
               
                 1% polyoxyl 40 
                 buffer 
                 3 
                 5 
               
               
                 hydrogenated castor oil 
                 sodium chloride 
                   
                   
               
               
                 (Cremophor RH 40) 
                 water 
                   
                   
               
               
                 1% Polysorbate 80 
                 sodium choride 
                 4 
                 5 
               
               
                 (Tween 80) 
                 water 
                   
                   
               
               
                 1% Poloxamine 1107 
                 sodium choride 
                 2 
                 5 
               
               
                 (Tetronic 1107) 
                 water 
                   
                   
               
               
                 1% Poloxamer 407 
                 sodium choride 
                 2 
                 5 
               
               
                 (Pluronic F127) 
                 water 
                   
                   
               
               
                 1% Polysorbate 80 
                 buffer 
                 3 
                 5 
               
               
                 (Tween 80) 
                 sodium chloride 
                   
                   
               
               
                   
                 water 
                   
                   
               
               
                 1% Poloxamine 1107 
                 buffer 
                 1 
                 5 
               
               
                 (Tetronic 1107) 
                 sodium chloride 
                   
                   
               
               
                   
                 water 
                   
                   
               
               
                 1% Poloxarner 407 
                 buffer 
                 1 
                 5 
               
               
                 (Pluronic F127) 
                 sodium chloride 
                   
                   
               
               
                   
                 water 
                   
                   
               
               
                 Water 
                 water 
                 1 
                 5 
               
               
                   
               
               
                 Key 
               
               
                 1 non-spreading drop 
               
               
                 2 poor spreading drop 
               
               
                 3 moderate spreading drop 
               
               
                 4 increased spreading drop 
               
               
                 5 thin spreading film 
               
             
          
         
       
     
         [0015]    The results demonstrates that exposure of the contact lens to the ethoxylated glyceride will generate a durable modified surface capable of allow the formation of a thin oil and aqueous film. This characteristic mimics mucin and is essential for the proper tear layer formation of over the lens. A score of 3 or better is considered acceptable. This experiment also illustrates the synergistic improvement when the ethoxylated glyceride is exposed in the presence of a buffer. The inability of the Poloxamer and Poloxamine to allow the oil film to spread across the lens demonstrates that not all surface active agents will promote the spreading of a properly formed tear film over the contact lens, surface. 
       EXAMPLE 2 
     Example of Protein Deposition Inhibition 
       [0016]    Contact lenses were soaked and heated in test solutions to which a radio-labeled lysozyme was present in a known amount for a period of 12 hours at 37 degrees Celsius. The lenses were rinsed with distilled water in order to remove residual solution. The lenses were then assayed for protein deposition using a Beckman BioGamma 1 counter. Results were reported in ug/lens. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
               
               
                   
                 Lens A 
                 Lens B 
                 Average 
               
               
                   
                 ug/lens 
                 ug/lens 
                 ug/lens 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Phosphate buffer control 
                 1,043 
                 865 
                 954 
               
               
                 Cremophor RH40 (1%) 
                 15 
                 23 
                 19 
               
               
                 In Phosphate Buffer 
               
               
                   
               
             
          
         
       
     
         [0017]    Ethoxylated Castor Oil was a 1 percent w/v solution. The matrix control was phosphate buffer and sodium chloride. The polyoxyl 40 hydrogenated castor oil solution had lower protein binding than the control. 
       EXAMPLE 3 
     Example of Protein Deposition Inhibition 
       [0018]    Isotonic aqueous phosphate buffered solutions were prepared and adjusted to pH 7.4. Contact lenses were soaked in 25 mL of the test solutions overnight. Afterwards, lysozyme was added to the tubes and warmed to 37 degrees Celsius for 12 hours. The lenses were rinsed with distilled water in order to remove residual solution. The lenses were assayed for protein deposition by the RCA method and detected on an HP PDA Spectrophotometer. Results were reported in ug/lens. 
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
               
               
                   
                 Solution 
                 ug lysozyme per lens 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Marketed Product Control 
                 &gt;18.3 
               
               
                   
                 (phosphate buffer, Poloxamer) 
                   
               
               
                   
                 Phosphate buffer control 
                 &gt;26.16 
               
               
                   
                 Cremophor RH40 (1%) 
                 9.78 
               
               
                   
                 In Phosphate Buffer 
               
               
                   
               
             
          
         
       
     
         [0019]    Ethoxylated Castor Oil was a 1 percent w/v solution. The matrix control was phosphate buffer and sodium chloride. The polyoxyl 40 hydrogenated castor oil solution had lower protein binding than the control. 
       EXAMPLE 4 
       [0020]    An example of a preferred disinfecting formulation of the subject invention is provided below in Table 1. This solution is prepared by weighing out the necessary amount of the tricine, creatine, choline chloride, sodium chloride and edetate disodium into a vessel containing approximately 90% of the water volume. After each of the ingredients has dissolved, the pH is adjusted to 7.3 with either 1 N sodium hydroxide or 1 N hydrochloric acid. Following this, the polyhexamethylene biguanide is added and the solution is brought to final volume with purified water. The final product has the composition shown in the Table below. 
         [0000]    
       
         
               
               
               
             
           
               
                   
               
               
                   
                   
                 Weight/ 
               
               
                 Constituent 
                   
                 Volume 
               
               
                   
               
             
             
               
                 Polyhexamethylenebiguanide  
                 20% w/w solution 
                 0.0001% 
               
               
                 HCl 
                 available under the mark 
                   
               
               
                   
                 Cosmocil CQ, from 
                   
               
               
                   
                 Avecia 
                   
               
               
                 Tricine 
                 Spectrum 
                   1.0% 
               
               
                 Creatine 
                 Spectrum 
                  0.25% 
               
               
                 Choline Chloride 
                 Amersco 
                   0.5% 
               
               
                 Edetate Disodium 
                 Spectrum 
                  0.055% 
               
               
                 Polyoxyl 40 Hydrogenated  
                 Cremophor RH 40 from 
                   0.1% 
               
               
                 Castor Oil 
                 BASF Co. 
                   
               
               
                 Sodium Chloride 
                 Fisher Scientific 
                 As required for 
               
               
                   
                   
                 tonicity  
               
               
                   
                   
                 adjustment 
               
               
                   
                   
                 300 mOsm 
               
               
                 Hydrochloride Acid, IN 
                 VWR 
                 as required  
               
               
                   
                   
                 for pH adjust- 
               
               
                   
                   
                 ment to 7.3 
               
               
                 Sodium Hydroxide, 1N 
                 Mallinckrodt 
                 as required  
               
               
                   
                   
                 for pH adjust-  
               
               
                   
                   
                 ment to 7.3 
               
               
                 Purified Water 
                   
                 Balance to  
               
               
                   
                   
                 100% 
               
               
                   
               
             
          
         
       
     
         [0021]    This solution may be used to rinse, clean, and store contact lenses on a daily basis. 
       EXAMPLE 5 
       [0022]    An example of a preferred formulation for a contact lens vial storage of the subject invention is provided below in Table I. This solution is prepared by weighing out the necessary amount of the sodium borate, boric acid, and sodium chloride into a vessel containing approximately 90% of the water volume. After each of the ingredients has dissolved, the pH is adjusted to 7.3 with either 1 N sodium hydroxide or 1 N hydrochloric acid. The final product had the composition shown in Table I below. 
         [0000]    
       
         
               
               
               
             
           
               
                   
               
               
                   
                   
                 Weight/ 
               
               
                 Constituent 
                   
                 Volume 
               
               
                   
               
             
             
               
                 Sodium Borate 
                 Spectrum 
                  1.0% 
               
               
                 Boric Acid 
                 Spectrum 
                 0.25% 
               
               
                 Polyoxyl 40 Hydrogenated 
                 Cremophor RH40  
                  0.1% 
               
               
                 Castor Oil 
                 from BASF 
                   
               
               
                 Sodium Chloride 
                 Fisher Scientific 
                 As required for 
               
               
                   
                   
                 tonicity adjustment 
               
               
                   
                   
                 300 mOsm 
               
               
                 Hydrochloride Acid, 1N 
                 VWR 
                 as required for pH 
               
               
                   
                   
                 adjustment to 7.3 
               
               
                 Sodium Hydroxide, IN 
                 Mallinckrodt 
                 as required for pH 
               
               
                   
                   
                 adjustment to 7.3 
               
               
                 Purified Water 
                   
                 Balance to 100% 
               
               
                   
               
             
          
         
       
     
       EXAMPLE 6 
       [0023]    The following are useful disinfecting solutions within the scope of the present invention that may be used for all purpose disinfecting solutions. They are made according to generally acceptable procedures except that the ethoxylated glycerides must be first be dissolved in warm water prior to the addition of the other components. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
             
           
               
                   
               
               
                   
                   
                 % Weight/ 
                   
               
               
                 Constituent 
                 Supplier 
                 Volume 
                 Amount 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Purified Water 
                   
                 to 80% 
                 40  
                 mL 
               
               
                 Tricine 
                 Spectrum 
                   1.0% 
                 0.500  
                 g 
               
               
                 Carnitine 
                 Spectrum 
                   .25% 
                 0.125  
                 g 
               
               
                 Betaine HCl 
                 Spectrum 
                   0.1% 
                 0.050  
                 g 
               
               
                 Choline Chloride 
                 Amresco 
                   0.5% 
                 0.250  
                 g 
               
               
                 Inositol 
                 Spectrum 
                   0.1% 
                 0.050  
                 g 
               
               
                 Edetate Disodium 
                 Spectrum 
                  0.055% 
                 0.0275  
                 g 
               
               
                 Polyoxyl 40 
                 Cremophor  
                   0.1% 
                 0.5  
                 mL of 10% 
               
             
          
           
               
                 Hyrdogenated  
                 RH 40 from  
                   
                   
               
               
                 Castor Oil 
                 BASF Co. 
                   
                   
               
               
                 Hydrochloride  
                   
                 As required for pH 
                 As required for pH 
               
               
                 Acid, 1N 
                   
                 adjustment to 7.3 
                 adjustment to 7.3 
               
               
                 Sodium  
                   
                 As required for pH 
                 As required for pH 
               
               
                 Hydroxide, 1N 
                   
                 adjustment to 7.3 
                 adjustment to 7.3 
               
               
                 Purified Water 
                   
                 To 98% 
                 Dilute to 49 mL 
               
               
                 Sodium Chloride 
                 Fisher 
                 As required for 
                 As required for 
               
               
                   
                   
                 tonicity  
                 tonicity  
               
               
                   
                   
                 adjustment 
                 adjustment 
               
               
                   
                   
                 300 mOsm 
                 300 mOsm 
               
             
          
           
               
                 Polyhexameth- 
                 20% w/w so- 
                 0.0001% 
                 50  
                 uL of 0.1% 
               
             
          
           
               
                 ylene- 
                 lution avail- 
                   
                   
               
               
                 biguanide 
                 able under  
                   
                   
               
               
                 HCl 
                 the mark  
                   
                   
               
               
                   
                 Cosmocil CQ  
                   
                   
               
               
                   
                 from Avecia 
                   
                   
               
               
                 Purified Water 
                   
                 Balance to 100% 
                 Dilute to 50 mL 
               
               
                   
               
             
          
         
       
     
       EXAMPLE 7 
       [0024]    The following are formulations within the scope of the invention of formulations intended to be used as lens-vial solutions that are used to store lenses prior to their use. These solutions have the effect of treating the contact lens in the solution and rendering the lens more comfortable in use. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
             
           
               
                   
               
               
                   
                   
                 % Weight/ 
                   
               
               
                 Constituent 
                 Supplier 
                 Volume 
                 Amount 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Purified  
                   
                 To 80% 
                 40  
                 mL 
               
               
                 Water 
                   
                   
                   
                   
               
               
                 Tricine 
                 Spectrum 
                  1.0% 
                 0.500  
                 g 
               
               
                 Carnitine 
                 Spectrum 
                 0.25% 
                 0.125  
                 g 
               
               
                 Inositol 
                 Spectrum 
                  0.1% 
                 0.050  
                 g 
               
             
          
           
               
                 Hydrochloride  
                   
                 As required for pH 
                 As required for pH 
               
               
                 Acid, 1N 
                   
                 adjustment to 7.3% 
                 adjustment to 7.3% 
               
               
                 Sodium  
                   
                 As required for pH 
                 As required for pH 
               
               
                 Hydroxide,  
                   
                 adjustment to 7.3% 
                 adjustment to 7.3% 
               
               
                 1N 
                   
                   
                   
               
             
          
           
               
                 Polyoxyl 40 
                 Cremophor  
                  0.1% 
                 0.5  
                 mL of 10% 
               
             
          
           
               
                 Hydrogenated  
                 RH 40 from  
                   
                   
               
               
                 Castor Oil 
                 BASF Co. 
                   
                   
               
               
                 Purified Water 
                   
                 To 98% 
                 Dilute to 49 mL 
               
               
                 Sodium  
                 Fisher 
                 As required for 
                 As required for 
               
               
                 Chloride 
                   
                 tonicity adjustment 
                 tonicity adjustment 
               
               
                   
                   
                 300 mOsm 
                 300 mOsm 
               
               
                 Purified Water 
                   
                 Too 100% 
                 Dilute to 50 mL