Abstract:
The use of multifunctional synthetic compounds to both stabilize and preserve therapeutic emulsions is described. The multifunctional synthetic compounds have unique molecular arrangement wherein a phosphate group is linked to one, two or three quaternary ammonium functionalities via a substituted propenyl group, and each quaternary ammonium functionality is further linked to at least one hydrocarbon chain. The pharmaceutical emulsions which include these multifunctional compounds may be prepared without heating or homogenization, and may not require the use of any additional stabilizing or preserving agents.

Description:
CROSS-REFERENCE TO RELATED APPLICATION 
       [0001]    This application claims priority under 35 U.S.C. §119 to U.S. Provisional Patent Application No. 61/056,675, filed May 28, 2008, the entire contents of which are incorporated herein by reference. 
     
    
     TECHNICAL FIELD 
       [0002]    The present invention relates to emulsions for topical or internal use, particularly for ocular, intraocular, otic, and/or nasal applications. The present invention also relates to methods of both preserving and stabilizing such emulsions. The emulsions are particularly intended for use in ophthalmic drug delivery, and may be useful to increase the drug concentration or to enhance the bioavailability of hydrophobic drugs. The emulsions of the present invention are typically stable, non-irritating to ocular tissues, meet international preservation standards or a combination thereof. 
       BACKGROUND 
       [0003]    Although ophthalmic drugs are typically delivered to the eye in aqueous solutions, many drugs which are therapeutically useful are insufficiently soluble in an aqueous vehicle to be provided in solution form. Alternative dosage forms for these lipid-soluble agents include ointments, suspensions and emulsions. Emulsions, particularly of the oil in water type, provide a means to deliver hydrophobic drugs either to the ocular surface or intraocularly. Although use of emulsions has been limited based on their difficulty of formulation, challenges with preservation, and comfort and irritation issues, there has been increasing interest in emulsions and microemulsions for ophthalmic use. 
         [0004]    Broadly, emulsions are blended mixtures of two or more normally immiscible substances, usually fluids. In forming an emulsion, one substance is dispersed in the other. For example, in forming an oil-in-water emulsion, oil (the dispersed phase) is dispersed into water (termed the continuous phase). 
         [0005]    Emulsions do not form spontaneously. Emulsions require some form of energy input, for example, stirring, shaking or spraying, in order to be formed. Intensive mixing of this nature is sometimes termed homogenization. Emulsions are also typically unstable. Over time, emulsions tend to separate into the more stable state of separation, for example, oil and water. Surface active agents, termed emulsifiers in this context, can increase the kinetic stability of emulsions. Many physical and chemical methods are used to prepare and stabilize emulsions, for example by heating, homogenization, and adding thickening agents, to name a few. However, use of these methods can add to the complexity, time and expense of preparing emulsions. 
         [0006]    Compositions, including emulsions, intended for pharmaceutical use typically include preservatives to prevent or retard microbial contamination. Choice of a particular preservative or biocidal agent is usually closely tied to the intended application area. For example, for topical ophthalmic use, preservation is frequently accomplished by using a biocidal agent selected from a limited number of chemical classes, based on their relative safety and efficacy. Ophthalmic biocides typically fall into one of the following chemical classes: biguanides, quaternary ammonium compounds, polyamines and amides. 
         [0007]    Various methods of testing are in use in order to ensure the safety of such products. For example, the United States Pharmacopeia (USP), a compendium of quality control tests for drugs and excipients used in medicinal formulations includes an antimicrobial effectiveness test (AEP), based on products and their route of administration. In the USP AEP, category 2 applies to topically used products made with aqueous bases or vehicles, non-sterile nasal products, and emulsions, including those applied to mucous membranes. An alternative, in some ways more stringent, testing method is detailed in the European Pharmacopoeia (Ph. Eur.) and the British Pharmacopeia (BP). 
         [0008]    According to the United States Pharmacopoeia (USP Chapter 1151), “all emulsions require an antimicrobial agent because the aqueous phase is favorable to the growth of microorganisms”. It is often difficult to preserve emulsions, in part due to the partitioning of the antimicrobial agent from the aqueous phase. 
         [0009]    Emulsions intended for pharmaceutical use must also demonstrate a measure of physical stability. That is, there should be little or no evidence of creaming or separation upon storage. 
         [0010]    Emulsifiers, or emulsion stabilizers, are frequently used to stabilize the dispersion of oil. The interactions between the emulsifier and the composition can be complex, as the emulsifier may modify the interface, as well as the environments of either or both phases. 
         [0011]    Thickening agents may also be used to stabilize emulsions. Various polymers are also used to stabilize emulsions, functioning either as thickening agents, or to form structured interfacial films to prevent coalescence. 
         [0012]    Several prior references teach agents with antimicrobial or other properties. U.S. Pat. Nos. 4,209,449 and 4,503,002 (Mayhew et al.) describe phosphate quaternary compounds. U.S. Pat. No. 4,215,064 describes phosphobetaines. PCT Appl. No. 2006/029255 (Scholz) describe cationic antiseptic compositions. U.S. Pat. No. 6,120,758 (Siddiqui et al.) describes preservatives systems for topically applied products. Each of these references are fully incorporated herein by reference for all purposes. 
       SUMMARY OF THE INVENTION 
       [0013]    Surprisingly, emulsions have now been discovered that exhibit a combination or all of the following characteristics: they do not require heating, homogenization or thickening agents for emulsion stabilization, they pass European Pharmacopoeial testing paradigms, they can be manufactured without elaborate or special equipment, and/or they do not require an added preservative. Furthermore, the emulsions of the present invention are typically not irritating to ocular tissues, nor are they uncomfortable upon topical ocular administration. Thus, the present invention relates to emulsions that are typically stable, comfortable, low-irritancy, self-preserved or any combination thereof. The emulsions of the present invention are useful, inter alia, for the delivery of therapeutic pharmaceuticals. Among other factors, the present invention is based upon the discovery that certain multifunctional synthetic compounds can uniquely perform the dual function of both stabilizing and preserving pharmaceutical emulsions, and can provide an emulsion that is comfortable and non-irritating and/or can be suitable, inter alia, for topical use, for example, to deliver therapeutic agents to eye, ear, or nasal passages or tissues. 
         [0014]    In preferred embodiments, the emulsions of the present invention have sufficient preservation efficacy so that the emulsions pass one or more standard preservative efficacy tests, such as the United States Preservative Efficacy Test (USPET), the European Preservative Efficacy Test-A (EP-A), the European Preservative Efficacy Test-B (EP-B), and similar standard tests. Most preferably, the emulsions of the present invention are sufficiently preserved so that they are able to pass one or more of these tests without the inclusion of a conventional preserving agent. 
         [0015]    The present invention is based in part on the finding that certain multifunctional synthetic compounds are capable of performing the dual function of acting both as a preserving agent for emulsion compositions and also as an emulsion stabilizer. The multifunctional synthetic compounds have a unique molecular arrangement wherein a phosphate group is linked to one, two or three quaternary ammonium functionalities via a substituted propenyl group, and each quaternary ammonium functionality is further linked to at least one hydrocarbon chain. Without wishing to be bound by theory, it is believed that it is this unique molecular arrangement that enables these compounds to impart desired properties, including preservation and stabilization, to the emulsions of the present invention. The present invention is based in part as well on the additional finding that the emulsion compositions stabilized and preserved with these multifunctional synthetic compounds are both comfortable and non-irritating to the eye. The emulsions of the present invention can be prepared without the use of heat, homogenization or thickening agents. 
     
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         [0016]      FIG. 1A  is a histogram of the initial emulsion particle size measurements for Formulation B. 
           [0017]      FIG. 1B  is a histogram of Formulation B emulsion particle size measurements at 60 weeks. 
           [0018]      FIG. 2A  is a histogram of the initial emulsion particle size measurements for Formulation C. 
           [0019]      FIG. 2B  is a histogram of Formulation C emulsion particle size measurements at 62 weeks. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0020]    The present invention is directed to emulsions containing compounds of the formula: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein:
 
x is 1 to 3 or mixtures thereof;
 
x+y is equal to 3;
 
a is 0 to 2;
 
z is equal to x;
 
       B is O— or OM; 
       [0021]    A is an anion;
 
M is a cation;
 
Y is selected from the group consisting of OH, O—C 1 -C 10  alkyl and O—C 1 -C 10  alkenyl; and
 
R1, R2 and R3 are the same or different and are alkyl, substituted alkyl, alkyl aryl or alkenyl groups, optionally interrupted by —NHC(═O)—, of up to 16 carbon atoms with the proviso that the total carbon atoms in R1+R2+R3 is between 10 and 24.
 
         [0022]    In the foregoing definitions of R1, R2, R3, A, M and Y substituents, and throughout, the following terms unless otherwise indicated, shall be understood to have the following meanings: 
         [0023]    The term “alkenyl” includes straight or branched chain hydrocarbon groups having 1 to 30 carbon atoms with at least one carbon-carbon double bond, the chain being optionally interrupted by one or more heteroatoms. The chain hydrogens may be substituted with other groups, such as, halo, —CF 3 , —NO 2 , —NH 2 , —CN, —OCH 3 , —C 6 H 5 , —C 6 H 5 O-alkyl, —O—C 6 H 5 O-alkenyl, p-NHC(═O)—C 6 H 5 —NHC(═O)—CH 3 , —CH═NH, NHC(═O)-Ph and —SH. Preferred straight or branched alkenyl groups include allyl, ethenyl, propenyl, butenyl, pentenyl, hexenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl or hexadecenyl. 
         [0024]    The term “alkyl” includes straight or branched chain aliphatic hydrocarbon groups that are saturated and have 1 to 30 carbon atoms. The alkyl groups may be interrupted by one or more heteroatoms, such as oxygen, nitrogen, or sulfur, and may be substituted with other groups, such as, halo, —CF 3 , —NO 2 , —NH 2 , —CN, —OCH 3 , —C 6 H 5 , —C 6 HsO-alkyl, —O—C 6 H 5 O-alkenyl, p-NHC(═O)—C 6 H 5 —NHC(═O)—CH 3 , —CH═NH, —NHC(═O)-Ph and —SH. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, sec-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl or hexadecyl. 
         [0025]    The term “halo” means an element of the halogen family. Preferred halo moieties include fluorine, chlorine, bromine or iodine. 
         [0026]    The present invention is also directed to methods of both preserving and stabilizing pharmaceutical emulsions using compounds of formula (I). 
         [0000]    The preferred compounds of formula (I) are those wherein
 
R1 and R2 are independently C 1 -C 6  alkyl;
 
R3 is C 6 -C 16  alkyl, optionally interrupted by —NHC(═O)—;
 
x is 2;
 
a is 1;
 
       B is O − ; 
       [0027]    A is halo;
 
Y is selected from the group consisting of OH, O—C 1 -C 10  alkyl and O—C 1 -C 10  alkenyl; and
 
M is selected from the group consisting of sodium and potassium.
 
The more preferred compounds of formula (I) are identified as Compounds I-3 in the following table:
 
         [0000]                                        SUBSTITUENT   COMPOUND 1   COMPOUND 2   COMPOUND 3                   R1   —CH 3     —CH 3     —CH 3         R2   —CH 3     —CH 3     —CH 3         R3   —(CH 2 ) 11 CH 3     —(CH 2 ) 3 —NHC(═O)—(CH 2 ) 10 CH 3     —(CH2) 3 —NHC(═O)—(CH 2 ) 12 CH 3         A   Cl −     Cl −     Cl −         M   Na +     Na +     Na +         Y   —OH   —OH   —OH       x   2   2   2       y   1   1   1       B   —O −     —O −     —O −                      
Compound 1 is the most preferred compound of formula (I). Compound 1 is also designated as sodium coco-diimonium chloride phosphate (SCDCP) in this application.
 
         [0028]    The compounds of formula (I) can be synthesized in accordance with known procedures (see for example, U.S. Pat. Nos. 5,286,719; 5,648,348 and 5,650,402, which are fully incorporated herein by reference for all purposes), and/or purchased from commercial sources, such as Uniqema (Cowick Hall, Snaith Goole, East Yorkshire (UK) DN14 9AA). 
         [0029]    The emulsions of the present invention contain one or more compounds of formula (I) in an amount sufficient to both stabilize and preserve the emulsion. In general, the amount of compound of formula (I) will be at least 0.005% but less than 5.0%, preferably 0.05 to 0.5%, more preferably 0.1 to 0.2%. 
         [0030]    Embodiments of the present invention include self-stabilizing self-preserved pharmaceutical emulsions. The term self-stabilizing means that the emulsion is made up of materials which alone would not serve to provide a stable emulsion, however, due to the addition of the compounds of formula (I), it is possible to form a stable emulsion. In some embodiments, the emulsions are free of additional stabilizing agents. In other embodiments, the emulsions are substantially free of conventional stabilizing agents, i.e., while they may contain small amounts of stabilizing agents, the amounts are generally less than would be required of emulsions which do not include the compounds of formula (I), for example, less than about 2 w/v %. In still other embodiments, conventional stabilizing agents are included to improve or optimize properties of the emulsions. 
         [0031]    The term self-preserved means that, due to the compounds of formula (I), the inclusion of conventional preservatives is typically not necessary for effective preservation of the emulsions. In some embodiments, the emulsions are free of conventional preserving agents. In other embodiments, the emulsions are substantially free of conventional preservatives, i.e., while they may contain small amounts of conventional antimicrobial agents, the amounts are generally less than would be required of emulsions which do not include the compounds of formula (I), for example, less than about 0.01 w/v %. In still other embodiments, conventional preserving agents are included to improve or optimize the preservation of the emulsions. 
         [0032]    In this context, conventional preserving agents include, without limitation, benzalkonium chloride, benzalkonium bromide, benzethonium chloride, benzyl alcohol, phenylethyl alcohol, cetrimide, polyquaternium-1, chlorhexidine, chlorobutanol, cetylpyridinium chloride, parabens, thimerosal, chlorine dioxide, stabilized oxychloro compounds, PVP-Iodine complex, polyhexamethylene biguanide, alexidine, N-alkyl-2-pyrrolidone, hexetidine, sorbic acid, potassium sorbate, N,N-dichlorotaruine and mercurial preservatives. 
         [0033]    The ophthalmic, otic and nasal emulsions of the present invention will be formulated so as to be compatible with the tissues of the eye, ear or nose. For example, as will be appreciated by those skilled in the art, ophthalmic compositions intended for direct application to the eye will usually be formulated so as to have a pH and tonicity, i.e., osmolality, that are compatible with the eye. The preferred pH for the ophthalmic emulsions of the present invention ranges from about 4.5 to about 9, more preferably from about 5 to about 8. The preferred range of osmolality for the ophthalmic emulsions of the present invention is from about 200 to about 350 milliOsmoles per kilogram (mOsm/kg). 
         [0034]    Although polymers may not be required to stabilize the emulsions of the present invention, they may be added, for example, in artificial tear or dry eye formulations. Suitable polymers for use with the emulsions of the present invention include, but are not limited to, Carboxymethylcellulose (CMC), Guar, Hydroxypropyl Guar (HP Guar), Dextran, Xanthan and HPMC. 
         [0035]    Osmolytes may be added. Suitable osmolytes include, but are not limited to, sorbitol, mannitol, dextran, propylene glycol and glycerin. 
         [0036]    Corn Oil may be employed as the lipid or oil phase of the emulsion. Other oils can be used as well, for example, medium-chain triglyceride (MCT) oil, sesame oil, cottonseed oil, mineral oil or olive oil. 
         [0037]    Boric acid may be used as a buffering agent. Other suitable buffering agents may be used in appropriate concentrations, for example, phosphates, acetate, tromethamine or citrate. 
         [0038]    Polyoxyl-40 Hydrogenated Castor Oil (HCO-40) may be used as an emulsifier/surfactant. Other alternative emulsifiers may be used, but it may be necessary to match the hydrophilic-lipophilic balance of the emulsifier to avoid interaction with the compounds of formula (I) in order to maintain preservation. Alternative emulsifiers include poloxamines, e.g. poloxamine 1304 (“Tetronic 1304”), poloxamers (Pluronics) and glycerides. 
         [0039]    Unless otherwise indicated, all ingredient amounts expressed in percentage terms are presented as w/v %. 
         [0040]    The emulsions of the present invention optionally contain a therapeutically effective amount of a therapeutic or diagnostic agent. As utilized herein, the term “therapeutic agent” means a chemical or biological composition that causes a physiological effect for a therapeutic purpose. “Therapeutic agent” therefore encompasses any agent that treats or prevents a disease or pathological condition or otherwise promotes health, including, but not limited to, drug substances, antimicrobial agents, antiseptics, antibiotics, disinfectants, and antimicrobial peptides, genetic materials including any nucleic acids, nucleotides, nucleosides, proteins, etc. The term “therapeutic agent” encompasses the singular and the plural, and thus means either one therapeutic agent or more than one therapeutic agent. 
         [0041]    The therapeutic agent (also called drug compounds or active ingredients) that can be included in the emulsions of the present invention includes, but is not limited to, ophthalmic, otic or nasal agents that can be applied either topically or internally, for example, intraocularly. Such agents include, but are not limited to: antiglaucoma agents, anti-hypertensive agents, non-steroidal antiinflammatory agents, steroidal antiinflammatory agents, antibacterial agents, antiinfective agents, antifungal agents, antiviral agents, anticataract agents, antioxidant agents, antiallergic agents, antimetabolic agents, immunosuppresive agents, and growth factor agents. In certain embodiments of the present invention, the therapeutic agent is selected from the group comprising a receptor tyrosine kinase inhibitor (RTKi), a prostaglandin and an immunosuppressant. 
         [0042]    While the pharmaceutical emulsions of the present invention can be effectively preserved using one or more of the compounds of formula (I) without adding a conventional antimicrobial agents such as those described above, the emulsions of the present invention may also contain in addition one or more conventional preserving agent. To the emulsions of the present invention may be added, for example, a polymeric quaternary ammonium compound as described in U.S. Pat. No. 4,407,791 (Stark), the entire contents of which are hereby incorporated into the present specification by reference. The preferred polymeric quaternary ammonium compound is polyquaternium-1. Polymeric quaternary ammonium compounds are typically utilized in an amount of from about 0.00001 to 0.01%. For the agent polyquaternium-1, an amount of about 0.001% is typically preferred. 
         [0043]    As will be appreciated by those skilled in the art, the emulsions of the present invention may contain a wide variety of ingredients, such as tonicity agents (e.g., sodium chloride, propylene glycol, mannitol), surfactants (e.g., polysorbate, polyethoxylated castor oil (e.g. Cremophors), sorbitan fatty acid esters (e.g. Span), polyethylene glycol sorbitan fatty acid esters (e.g. Tweens) and polyoxyethylene-polyoxypropylene-polyoxyethylene copolymers), viscosity adjusting agents (e.g., hydroxypropyl methyl cellulose, other cellulose derivatives, gums and derivatives of gums), buffering agents (e.g., borates, citrates, phosphates, carbonates), comfort-enhancing agents (e.g., guar gum, xanthan gum and polyvinyl pyrrolidone), stabilizing agents (e.g., EDTA, nonyl-ethyenediaminetriacetic acid) and solublizing aids. 
         [0044]    The following examples further illustrate various embodiments of the invention. These examples are provided to aid in the understanding of the invention and are not to be construed as limitations thereof. 
       Example 1 
       [0045]    A representative sterile compounding procedure for preparing emulsions containing compounds of Formula (I), shown in Table 1A, is described as follows: 
         [0000]    1. Hydrate the compound of Formula (I) and HCO-40 (Polyoxy)-40 Hydrogenated Castor Oil) in purified water (50% of total batch size) and filter through a 0.2 μm filtering unit.
 
2. Combine Boric Acid and Sorbitol in 25% purified water, stir until homogeneous and filter through a 0.2 μm filtering unit.
 
3. Transfer content from step 1 to a beaker that will at least hold twice as much volume as total batch weight, filter Oil into the beaker using a 0.2 μm syringe filter and stir vigorously for 1 hour.
 
4. Add content from step 2 to content from step 3, qs to 95% with purified water and stir vigorously for 1 hour.
 
7. Using 20% Tris Stock Solution (S/S), adjust the pH accordingly.
 
8. Qs to 100% and continue to stir vigorously for ˜20 hours.
 
When adding a drug or therapeutic agent, combine with Oil and sonicate until homogeneous before filtering. The concentrations provided here are based on 100% of total batch weight. This procedure, or slightly modified variants thereof, was used to prepare the emulsions described in the examples that follow.
 
       Example 2 
       [0046]    The antimicrobial activity and stability of the formulations shown in Table 1A below, which contain either 0.1 or 0.2 (w/v %) of Compound 1 were evaluated. Table 1A also contains an emulsion formulation (Formulation C) consisting of Cyclosporin and Compound 1. Table 1B constitutes overall standard preservative efficacy test (PET Screen International) results along with the results of a visual assessment of physical stability of the emulsions. The data indicates that all the formulations passed global PET standards and the emulsions are stable. Histograms for Formulation B, showing the initial particle size measurements as well as 60 weeks, can be seen in  FIGS. 1A &amp; 1B . Similarly, histograms for Formulation C, containing 0.05% Cyclosporin, showing the initial particle size measurements as well as at 62 weeks, can be seen in  FIGS. 2A &amp; 2B . It is clear from the histograms that no significant change of the emulsion particle size took place over an extended period of storage, indicating emulsion stability. The microbiological evaluation was conducted by determining the extent to which the emulsions reduced an initial population of about 10 6  cfu/mL microorganisms over time. The abbreviation “cfu” means colony forming unit. In the PET Screen International, at 24 hours all bacteria including  S. aureus, P. aeruginosa  and  E. coli  showed 5 log reductions for 0.1% Compound 1 and 0.2% Compound 1. Similarly, at 7 days approximately 5 log reductions were observed for  C. albicans . Overall EPA requirement of preservation in all tested formulations was achieved. The microbiology results are provided in greater detail in Table 1C, where the results of the evaluation of five microorganisms are provided. 
         [0000]    
       
         
               
             
               
               
             
               
               
               
               
               
             
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 1A 
               
             
             
               
                   
               
               
                 FORMULATION COMPOSITIONS 
               
             
          
           
               
                   
                 FORMULATION 
               
             
          
           
               
                   
                 A 
                 B 
                 C 
                 D 
               
             
          
           
               
                 INGREDIENT 
                 Concentration (w/v %) 
               
               
                   
               
             
          
           
               
                 Compound 1 
                 0.2 
                 0.1 
                 0.1 
                 0.1 
               
               
                 Sorbitol 
                 0.33 
                 0.33 
                 0.33 
                 0.33 
               
               
                 Boric Acid 
                 1 
                 1 
                 1 
                 1 
               
               
                 HCO-40 
                 0.5 
                 0.5 
                 0.5 
                 0.5 
               
               
                 Corn Oil 
                 0.75 
                 0.75 
                 0.75 
                 0.75 
               
               
                 Cyclosporine 
                 None 
                 None 
                 0.05 
                 None 
               
               
                 20% Tris S/S* 
                 Ajust pH 
                 Ajust pH 
                 Ajust pH 
                 Ajust pH 
               
               
                   
                 7.2 
                 7.2 
                 7.2 
                 6.0 
               
               
                 Purified Water 
                 Qs to 100% 
                 Qs to 100% 
                 Qs to 100% 
                 Qs to 100% 
               
               
                   
               
               
                 *S/S = Stock Solution 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 1B 
               
             
             
               
                   
               
               
                 PHYSICAL AND MICROBIOLOGICAL PARAMETERS 
               
             
          
           
               
                   
                 FORMULATION 
               
             
          
           
               
                   
                 A 
                 B 
                 C 
                 D 
               
               
                   
                   
               
             
          
           
               
                 Final pH 
                 7.2 
                 7.2 
                 7.2 
                 6.0 
               
               
                 PET Screen 
                 Pass EPA a   
                 Pass EPA a   
                 Pass EPA a   
                 Pass EPA a   
               
               
                 Visual 
                 No visible 
                 Minimal 
                 No visible 
                 No visible 
               
               
                 Stability 
                 separation 
                 separation 
                 separation 
                 separation 
               
               
                   
                 after 11 days 
                 after 11 days 
                 after 63 
                 after 9 weeks 
               
               
                   
                 at 40° C. and 
                 at 40° C. and 
                 weeks at RT. 
                 at RT. 
               
               
                   
                 50° C. 
                 50° C., cleared 
               
               
                   
                 No visible 
                 upon 
               
               
                   
                 separation at 
                 inverting 
               
               
                   
                 RT for 60 
                 once. No 
               
               
                   
                 weeks. 
                 visible 
               
               
                   
                   
                 separation at 
               
               
                   
                   
                 RT for 60 
               
               
                   
                   
                 weeks. 
               
               
                   
               
               
                   a Projected to pass EPA based on PET screen results 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
               
               
             
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 1C 
               
             
             
               
                   
               
               
                 MICROBIOLOGY RESULTS 
               
             
          
           
               
                   
                 Formulation 
                   
               
             
          
           
               
                   
                 A 
                 B 
                 C 
                 D 
               
             
          
           
               
                   
                 Time/Test Organism 
                 Log Order Reduction 
               
               
                   
                   
               
             
          
           
               
                   
                  6 hour/ S. aureus   
                 N/A 
                 N/A 
                 4.9 
                 4.9 
               
               
                   
                 24 hour/ S. aureus   
                 5.0 
                 5.0 
                 4.9 
                 4.9 
               
               
                   
                  7 day/ S. aureus   
                 5.0 
                 5.0 
                 4.9 
                 4.9 
               
               
                   
                  6 hour/ P. aeruginosa   
                 N/A 
                 N/A 
                 5.0 
                 5.0 
               
               
                   
                 24 hour/ P. aeruginosa   
                 5.0 
                 5.0 
                 5.0 
                 5.0 
               
               
                   
                  7 day/ P. aeruginosa   
                 5.0 
                 5.0 
                 5.0 
                 5.0 
               
               
                   
                  6 hour/ E. coli   
                 N/A 
                 N/A 
                 4.9 
                 3.1 
               
               
                   
                 24 hour/ E. coli   
                 5.0 
                 5.0 
                 4.9 
                 5.0 
               
               
                   
                  7 day/ E. coli   
                 5.0 
                 5.0 
                 4.9 
                 5.0 
               
               
                   
                  7 day/ C. albicans   
                 5.0 
                 5.0 
                 5.0 
                 4.9 
               
               
                   
                  7 day/ A. niger   
                 3.9 
                 3.9 
                 2.8 
                 2.6 
               
               
                   
                   
               
               
                   
                 *N/A = Not applicable 
               
             
          
         
       
     
       Example 3 
       [0047]    The stability and antimicrobial activity of the formulations shown in Table 2A below, which contain either 0.1, 0.2 (w/v %) of Compound 1, or have no added compound of Formula (I), were evaluated. The results, shown in Table 2B below, demonstrate the is stabilizing effect of adding the compound of Formula (I) to the emulsions. 
         [0000]    
       
         
               
             
               
               
             
               
               
               
               
             
               
               
             
               
               
               
               
             
           
               
                 TABLE 2A 
               
             
             
               
                   
               
               
                 FORMULATION COMPOSITIONS 
               
             
          
           
               
                   
                 FORMULATION 
               
             
          
           
               
                   
                 A 
                 B 
                 E 
               
             
          
           
               
                 INGREDIENTS 
                 Concentration (w/v %) 
               
               
                   
               
             
          
           
               
                 Compound 1 
                 0.2 
                 0.1 
                 None 
               
               
                 Sorbitol 
                 0.33 
                 0.33 
                 0.33 
               
               
                 Boric Acid 
                 1 
                 1 
                 1 
               
               
                 HCO-40 
                 0.5 
                 0.5 
                 0.5 
               
               
                 Corn Oil 
                 0.75 
                 0.75 
                 0.75 
               
               
                 20% Tris S/S* 
                 Adjust pH 7.2 
                 Adjust pH 7.2 
                 Adjust pH 7.2 
               
               
                 Purified Water 
                 Qs to 100% 
                 Qs to 100% 
                 Qs to 100% 
               
               
                   
               
               
                 *S/S = Stock Solution 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 2B 
               
             
             
               
                   
               
               
                 PHYSICAL PARAMETERS 
               
             
          
           
               
                   
                 FORMULATION 
               
             
          
           
               
                   
                 A 
                 B 
                 E 
               
               
                   
                   
               
             
          
           
               
                 Final pH 
                 7.2 
                 7.2 
                 7.2 
               
               
                 PET Screen 
                 PASS EPA a   
                 PASS EPA a   
                 N/A 
               
               
                 Visual 
                 No visible 
                 Minimal separation 
                 Very milky and 
               
               
                 Stability 
                 separation after 11 
                 after 11 days at 
                 creamy. Upon 
               
               
                   
                 days at 40° C. and 
                 40° C. and 50° C., 
                 allowing to sit 
               
               
                   
                 50° C. No visible 
                 cleared upon 
                 overnight there 
               
               
                   
                 separation at RT 
                 inverting once. No 
                 was 
               
               
                   
                 for 60 weeks. 
                 visible separation 
                 significant 
               
               
                   
                   
                 at RT for 60 weeks 
                 separation. 
               
               
                   
               
               
                   a Projected to pass EPA 
               
             
          
         
       
     
       Example 4 
       [0048]    Stability measurements of the formulation with higher amount of corn oil (1%) shown in Table 3A are provided in Table 3B below. 
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 3A 
               
             
             
               
                   
               
               
                 EMULSION FORMULATIONS WITH 1% CORN OIL 
               
             
          
           
               
                   
                   
                 FORMULATION 
               
               
                   
                   
                 F 
               
               
                   
                 INGREDIENTS 
                 Concentration (w/v %) 
               
               
                   
                   
               
               
                   
                 Compound 1 
                 0.1 
               
               
                   
                 Sorbitol 
                 0.33 
               
               
                   
                 Boric Acid 
                 1 
               
               
                   
                 HCO-40 
                 0.5 
               
               
                   
                 Corn Oil 
                 1 
               
               
                   
                 20% Tris S/S* 
                 Adjust pH 
               
               
                   
                 Purified Water 
                 Qs to 100% 
               
               
                   
                 Final pH 
                 7.2 
               
               
                   
                   
               
               
                   
                 *S/S = Stock Solution 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
             
           
               
                 TABLE 3B 
               
               
                   
               
               
                 PHYSICAL PARAMETERS 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 FORMULATION 
                 F 
               
               
                 Visual Stability 
                 Particle size histogram showed multiple peaks at ~0.1, 
               
               
                   
                 0.4 &amp; 2 μm. No visible separation in samples stored at 
               
               
                   
                 RT for 55 weeks. 
               
               
                   
               
             
          
         
       
     
       Example 5 
       [0049]    Further stability test results for Formulation C containing 0.05% Cyclosporine as active ingredient are shown in Table 4 below. The emulsion was packaged in both low density polyethylene (LDPE) Droptainers and glass vials. LDPE containers were used to measure the weight loss, pH and osmolality. The glass vials were used to examine color and physical stability of the formulations. No significant change of pH and osmolality were noted in the formulation stored at RT and 40° C. However, samples stored at 60° C. showed some change of pH and osmolality. Visual assessment of emulsion at room temperature (RT) showed either a slight separation, which cleared upon inverting once, or no separation at 2, 4, 6 and 62 weeks (2w, 4w, 6w and 62w). No separation was discerned in samples stored at 40° C. and 60° C. for 2, 4 and 6 weeks. Emulsions stored at RT and 40° C. showed no change of color whereas formulations stored at 60° C. turned yellow. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
             
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 STABILITY RESULTS 
               
             
          
           
               
                   
                 Total Weight 
                   
                 Osmolality 
                   
                 Visual 
               
               
                   
                 Loss (%) 
                 pH 
                 (mOsm) 
                 Color 
                 Stability 
               
             
          
           
               
                   
                 Packaging 
               
             
          
           
               
                 Condition/Time 
                 LDPE 
                 LDPE 
                 LDPE 
                 Glass Vial 
                 Glass Vial 
               
               
                   
               
             
          
           
               
                 Initial 
                 N/A* 
                 7.2 
                 174 
                 Opalescent 
                 Stable, No 
               
               
                   
                   
                   
                   
                   
                 Separation 
               
             
          
           
               
                 RT 
                 2 w 
                 0.04 
                 7.1 
                 172 
                 Opalescent 
                 Slight 
               
               
                   
                   
                   
                   
                   
                   
                 separation, 
               
               
                   
                   
                   
                   
                   
                   
                 cleared upon 
               
               
                   
                   
                   
                   
                   
                   
                 inverting once. 
               
               
                   
                 4 w 
                 0.05 
                 7.07 
                 170 
                 Opalescent 
                 Slight 
               
               
                   
                   
                   
                   
                   
                   
                 separation, 
               
               
                   
                   
                   
                   
                   
                   
                 cleared upon 
               
               
                   
                   
                   
                   
                   
                   
                 inverting once. 
               
               
                   
                 6 w 
                 0.05 
                 7.09 
                 170 
                 Opalescent 
                 Stable, No 
               
               
                   
                   
                   
                   
                   
                   
                 Separation 
               
               
                   
                 62 w  
                 N/A 
                 7.07 
                 179 
                 Opalescent 
                 Stable, No 
               
               
                   
                   
                   
                   
                   
                   
                 Separation 
               
               
                 40° C. 
                 2 w 
                 0.17 
                 7.07 
                 171 
                 Opalescent 
                 Stable, No 
               
               
                   
                   
                   
                   
                   
                   
                 Separation 
               
               
                   
                 4 w 
                 0.36 
                 7.07 
                 171 
                 Opalescent 
                 Stable, No 
               
               
                   
                   
                   
                   
                   
                   
                 Separation 
               
               
                   
                 6 w 
                 0.41 
                 7.08 
                 171 
                 Opalescent 
                 Stable, No 
               
               
                   
                   
                   
                   
                   
                   
                 Separation 
               
               
                 60° C. 
                 2 w 
                 0.84 
                 6.93 
                 179 
                 Light Yellow 
                 Stable, No 
               
               
                   
                   
                   
                   
                   
                   
                 Separation 
               
               
                   
                 4 w 
                 1.69 
                 6.82 
                 187 
                 Yellow 
                 Stable, No 
               
               
                   
                   
                   
                   
                   
                   
                 Separation 
               
               
                   
                 6 w 
                 2.33 
                 6.77 
                 191 
                 Yellow 
                 Stable, No 
               
               
                   
                   
                   
                   
                   
                   
                 Separation 
               
               
                   
               
               
                 *N/A = Not applicable 
               
             
          
         
       
     
       Example 6 
       [0050]    A one-day exaggerated topical ocular irritation and comfort evaluation of three formulations was conducted. Three New Zealand White rabbits were assigned to each test group and one eye of each animal was selected for use. The formulations were administered in the test eye approximately every 30 minutes for a total of 10 doses. Immediately following the first and last dose, a comfort evaluation was performed. One hour after the last dose, the test eye was examined biomicroscopically. Twenty-four hours following the first dose, all animals were reexamined for general health. 
         [0000]    The formulations tested were as follows:
       1. 0.2% Compound 1 Emulsion (Formulation A whose composition is as shown in Table 1A above).   2. 0.1% Compound 1 Emulsion (Formulation B whose composition is as shown in Table 1A above).   3. 0.1% Compound 1 Emulsion with 0.05% Cyclosporine (Formulation C whose composition is as shown in Table 1A above).
 
The maximum possible scores are as indicated as follows:
       
 
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 Conjunctival Congestion (Conj. Cong.) 
                 3.0 
               
               
                   
                 Conjunctival Swelling (Conj. Swell.) 
                 4.0 
               
               
                   
                 Conjunctival Discharge (Conj. Disch.) 
                 3.0 
               
               
                   
                 Iritis 
                 4.0 
               
               
                   
                 Flare 
                 3.0 
               
               
                   
                 Light Reflex 
                 2.0 
               
               
                   
                 Corneal Cloudiness 
                 4.0 
               
               
                   
                 Corneal Area 
                 4.0 
               
               
                   
                 Fluorescein Intensity (Fluor. Inten.) 
                 4.0 
               
               
                   
                 Fluorescein Area (Fluor. Area) 
                 4.0 
               
               
                   
                 Comfort (CMFT) 
                 4.0 
               
               
                   
                   
               
             
          
         
       
     
         [0054]    The results of these studies, presented in Table 5A, 5B and 5C, in particular considering the exaggerating dosage regimen employed, indicate that these formulations are substantially comfortable and not adversely irritating to the eye upon topical ocular administration. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 5A 
               
             
             
               
                   
               
               
                 One-Day Topical Ocular Irritation and Comfort Evaluation Formulation A 
               
             
          
           
               
                   
                   
                   
                   
                 Total 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 Conj. 
                 Conj. 
                 Conj. 
                 Conj. 
                 Light 
                   
                   
                 Corneal 
                 Corneal 
                 Fluor. 
                 Fluor. 
                 1 st   
                 2 nd   
                 Total 
               
               
                   
                 Cong. 
                 Swell. 
                 Disch. 
                 Irrit. 
                 Reflex 
                 Flare 
                 Iritis 
                 Cloudy 
                 Area 
                 Inten. 
                 Area 
                 CMFT 
                 CMFT 
                 Comfort 
               
               
                   
               
               
                 MEAN 
                 0.7 
                 0.0 
                 0.0 
                 — 
                 0.3 
                 0.0 
                 0.0 
                 0.0 
                 0.0 
                 0.0 
                 0.0 
                 2.0 
                 2.0 
                 — 
               
               
                 INCIDENCE 
                 2/3 
                 0/3 
                 0/3 
                 — 
                 1/3 
                 0/3 
                 0/3 
                 0/3 
                 0/3 
                 0/3 
                 0/3 
                 3/3 
                 3/3 
                 — 
               
               
                 SEVERITY 
                 N/A 
                 N/A 
                 N/A 
                 Minimal 
                 Minimal 
                 None 
                 None 
                 None 
                 None 
                 None 
                 None 
                 N/A 
                 N/A 
                 Moderate 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 5B 
               
             
             
               
                   
               
               
                 One-Day Topical Ocular Irritation and Comfort Evaluation Formulation B 
               
             
          
           
               
                   
                   
                   
                   
                 Total 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 Conj. 
                 Conj. 
                 Conj. 
                 Conj. 
                 Light 
                   
                   
                 Corneal 
                 Corneal 
                 Fluor. 
                 Fluor. 
                 1 st   
                 2 nd   
                 Total 
               
               
                   
                 Cong. 
                 Swell. 
                 Disch. 
                 Irrit. 
                 Reflex 
                 Flare 
                 Iritis 
                 Cloudy 
                 Area 
                 Inten. 
                 Area 
                 CMFT 
                 CMFT 
                 Comfort 
               
               
                   
                   
               
             
          
           
               
                 MEAN 
                 0.3 
                 0.0 
                 0.0 
                 — 
                 0.0 
                 0.0 
                 0.0 
                 0.0 
                 0.0 
                 0.0 
                 0.0 
                 1.7 
                 1.3 
                 — 
               
               
                 INCIDENCE 
                 1/3 
                 0/3 
                 0/3 
                 — 
                 0/3 
                 0/3 
                 0/3 
                 0/3 
                 0/3 
                 0/3 
                 0/3 
                 3/3 
                 3/3 
                 — 
               
               
                 SEVERITY 
                 N/A 
                 N/A 
                 N/A 
                 Minimal 
                 None 
                 None 
                 None 
                 None 
                 None 
                 None 
                 None 
                 N/A 
                 N/A 
                 Minimal- 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 Moderate 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 5C 
               
             
             
               
                   
               
               
                 One-Day Topical Ocular Irritation and Comfort Evaluation Formulation C 
               
             
          
           
               
                   
                   
                   
                   
                 Total 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 Conj. 
                 Conj. 
                 Conj. 
                 Conj. 
                 Light 
                   
                   
                 Corneal 
                 Corneal 
                 Fluor. 
                 Fluor. 
                 1 st   
                 2 nd   
                 Total 
               
               
                   
                 Cong. 
                 Swell. 
                 Disch. 
                 Irrit. 
                 Reflex 
                 Flare 
                 Iritis 
                 Cloudy 
                 Area 
                 Inten. 
                 Area 
                 CMFT 
                 CMFT 
                 Comfort 
               
               
                   
                   
               
             
          
           
               
                 MEAN 
                 0.7 
                 0.0 
                 0.0 
                 — 
                 0.0 
                 0.0 
                 0.0 
                 0.0 
                 0.0 
                 0.0 
                 0.0 
                 1.7 
                 1.3 
                 — 
               
               
                 INCIDENCE 
                 1/3 
                 0/3 
                 0/3 
                 — 
                 0/3 
                 0/3 
                 0/3 
                 0/3 
                 0/3 
                 0/3 
                 0/3 
                 3/3 
                 3/3 
                 — 
               
               
                 SEVERITY 
                 N/A 
                 N/A 
                 N/A 
                 Minimal 
                 None 
                 None 
                 None 
                 None 
                 None 
                 None 
                 None 
                 N/A 
                 N/A 
                 Minimal- 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 Moderate 
               
               
                   
               
             
          
         
       
     
       Example 7 
       [0055]      
         [0000]    
       
         
               
             
               
               
               
             
           
               
                   
               
               
                 Self-Preserved Emulsion to Treat Dry Eye 
               
             
          
           
               
                   
                   
                 Formulation 
               
               
                   
                   
                 G 
               
               
                   
                 Components 
                 Amount (% w/v) 
               
               
                   
                   
               
               
                   
                 Cyclosporine 
                 0.05 
               
               
                   
                 Polyoxyl 40 Hydrogenated Castor Oil 
                 0.75 
               
               
                   
                 Compound No. 1 
                 0.1 
               
               
                   
                 MCT Oil 
                 2 
               
               
                   
                 Boric acid 
                 1 
               
               
                   
                 Sorbitol 
                 0.33 
               
               
                   
                 Propylene glycol 
                 0.7 
               
               
                   
                 Hydrochloric acid/Sodium hydroxide 
                 q.s. to pH 
               
               
                   
                 Purified water 
                 q.s. to 100% 
               
               
                   
                 pH 
                 6.0 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
             
           
               
                   
               
               
                 Self Preserved Emulsion to Treat Glaucoma 
               
             
          
           
               
                   
                   
                 Formulation 
               
               
                   
                   
                 H 
               
               
                   
                 Components 
                 Amount (% w/v) 
               
               
                   
                   
               
               
                   
                 Travoprost 
                 0.004 
               
               
                   
                 Polyoxyl 40 Hydrogenated Castor Oil 
                 0.75 
               
               
                   
                 Compound No. 1 
                 0.1 
               
               
                   
                 MCT Oil 
                 2 
               
               
                   
                 Boric acid 
                 1 
               
               
                   
                 Sorbitol 
                 0.33 
               
               
                   
                 Propylene glycol 
                 0.7 
               
               
                   
                 Mannitol 
                 0.5 
               
               
                   
                 Hydrochloric acid/Sodium hydroxide 
                 q.s. to pH 
               
               
                   
                 Purified water 
                 q.s. to 100% 
               
               
                   
                 pH 
                 6.0 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
             
           
               
                   
               
               
                 Self Preserved Emulsion to Treat Glaucoma 
               
             
          
           
               
                   
                   
                 Formulation 
               
               
                   
                   
                 I 
               
               
                   
                 Components 
                 Amount (% w/v) 
               
               
                   
                   
               
               
                   
                 Latanoprost 
                 0.005 
               
               
                   
                 Polyoxyl 40 Hydrogenated Castor Oil 
                 0.75 
               
               
                   
                 Compound No. 1 
                 0.1 
               
               
                   
                 MCT Oil 
                 2 
               
               
                   
                 Boric acid 
                 1 
               
               
                   
                 Sorbitol 
                 0.33 
               
               
                   
                 Propylene glycol 
                 0.7 
               
               
                   
                 Mannitol 
                 0.5 
               
               
                   
                 Hydrochloric acid/Sodium hydroxide 
                 q.s. to pH 
               
               
                   
                 Purified water 
                 q.s. to 100% 
               
               
                   
                 pH 
                 6.0 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
             
               
               
               
               
             
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 Preservative Efficacy Data of the Emulsions 
               
             
          
           
               
                   
                 Formulation 
               
             
          
           
               
                   
                 I 
                 H 
                 G 
               
             
          
           
               
                   
                 PET 
                 Log 10 Unit Reduction 
               
               
                   
                   
               
             
          
           
               
                   
                   S. aureus /6 h 
                 5.0 
                 5.0 
                 5.0 
               
               
                   
                   S. aureus /24 h 
                 5.0 
                 5.0 
                 5.0 
               
               
                   
                   S. aureus /7 d 
                 5.0 
                 5.0 
                 5.0 
               
               
                   
                   S. aureus /14 d 
                 5.0 
                 5.0 
                 5.0 
               
               
                   
                   S. aureus /28 d 
                 5.0 
                 5.0 
                 5.0 
               
               
                   
                   P. aerugin /6 h 
                 4.9 
                 4.9 
                 4.9 
               
               
                   
                   P. aerugin /24 h 
                 4.9 
                 4.9 
                 4.9 
               
               
                   
                   P. aerugin /7 d 
                 4.9 
                 4.9 
                 4.9 
               
               
                   
                   P. aerugin /14 d 
                 4.9 
                 4.9 
                 4.9 
               
               
                   
                   P. aerugin /28 d 
                 4.9 
                 4.9 
                 4.9 
               
               
                   
                   E. coli /6 h 
                 5.0 
                 5.0 
                 5.0 
               
               
                   
                   E. coli /24 h 
                 5.0 
                 5.0 
                 5.0 
               
               
                   
                   E. coli /7 d 
                 5.0 
                 5.0 
                 5.0 
               
               
                   
                   E. coli /14 d 
                 5.0 
                 5.0 
                 5.0 
               
               
                   
                   E. coli /28 d 
                 5.0 
                 5.0 
                 5.0 
               
               
                   
                   C. albican /7 d 
                 4.9 
                 4.9 
                 4.9 
               
               
                   
                   C. albican /14 d 
                 4.9 
                 4.9 
                 4.9 
               
               
                   
                   C. albican /28 d 
                 4.9 
                 4.9 
                 4.9 
               
               
                   
                   A. niger /7 d 
                 3.7 
                 4.5 
                 4.6 
               
               
                   
                   A. niger /14 d 
                 5.1 
                 5.1 
                 5.1 
               
               
                   
                   A. niger /28 d 
                 5.1 
                 5.1 
                 5.1 
               
               
                   
                 RESULTS 
                 EPA 
                 EPA 
                 EPA 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 One-day Acute Ocular Safety/Comfort Study Data 
               
               
                 of Self-Preserved Emulsions 
               
             
          
           
               
                   
                   
                 Conj. 
                 Comfort 
                 Pass/ 
               
               
                 Formulation 
                 Description 
                 Irritation 
                 Score 
                 Fail 
               
               
                   
               
               
                 G 
                 0.05% Cyclosporine 
                 2.0 
                 4.0 
                 Pass 
               
               
                   
                 Self Preserved 
                 (Minimal) 
                 (Moderate) 
               
               
                   
                 Emulsion 
               
               
                 I 
                 0.005% Latanaprost 
                 2.0 
                 3.7 
                 Pass 
               
               
                   
                 Self Preserved 
                 (Minimal) 
                 (Moderate) 
               
               
                   
                 Emulsion 
               
               
                 H 
                 0.004% Travoprost Self 
                 1.8 
                 3.3 
                 Pass 
               
               
                   
                 Preserved Emulsion 
                 (Minimal) 
                 (Moderate) 
               
               
                   
               
             
          
         
       
     
       Example 8 
     A Representative Preserved Formulation 
       [0056]      
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
               
                   
                 Ingredient 
                 Amount (w/w %) 
               
               
                   
                   
               
             
             
               
                   
                 Active 
                   0-2.0% 
               
               
                   
                 Compound of Formula (I) 
                 0.001-1.0%  
               
               
                   
                 Sorbitol 
                 0.33% 
               
               
                   
                 Boric Acid 
                  1.0% 
               
               
                   
                 Corn Oil 
                 0.1-5.0% 
               
               
                   
                 HCO-40 
                 0.1-5.0% 
               
               
                   
                 20% Tromethamine S/S 
                 q.s. to pH 7.2 +/− 0.2 
               
               
                   
                 Purified Water 
                 q.s. 100% 
               
               
                   
                   
               
             
          
         
       
     
       Example 9 
     A Representative Preserved Formulation 
       [0057]      
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
               
                   
                 Ingredient 
                 Amount (w/w %) 
               
               
                   
                   
               
             
             
               
                   
                 Active 
                   0-2.0% 
               
               
                   
                 Compound of Formula (I) 
                 0.001-1.0%  
               
               
                   
                 Sorbitol 
                 0.33% 
               
               
                   
                 Boric Acid 
                  1.0% 
               
               
                   
                 MCT Oil 
                 0.1-5.0% 
               
               
                   
                 Tetronic 1304 
                 0.1-5.0% 
               
               
                   
                 20% Tromethamine S/S 
                 q.s. to pH 7.2 +/− 0.2 
               
               
                   
                 Purified Water 
                 q.s. 100% 
               
               
                   
                   
               
             
          
         
       
     
       Example 10 
     A Representative Preserved Formulation for Dry Eye Care 
       [0058]      
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
               
                   
                 Ingredient 
                 Amount (w/w %) 
               
               
                   
                   
               
             
             
               
                   
                 Active 
                   0-2.0% 
               
               
                   
                 Compound of Formula (I) 
                 0.001-1.0%  
               
               
                   
                 Guar Guma a   
                 0.16 
               
               
                   
                 Sorbitol 
                 0.33% 
               
               
                   
                 Boric Acid 
                  1.0% 
               
               
                   
                 MCT Oil 
                 0.1-5.0% 
               
               
                   
                 HCO 40 b   
                 0.1-5.0% 
               
               
                   
                 20% Tromethamine S/S 
                 q.s. to pH 7.2 +/− 0.2 
               
               
                   
                 Purified Water 
                 q.s. 100% 
               
               
                   
                   
               
               
                   
                   a could be replaced with hydroxypropyl guar gum 
               
               
                   
                   b other suitable surfactants such as Tween, Span, Cremophore etc. may also be used either alone or in combination 
               
             
          
         
       
     
         [0059]    The invention in its broader aspects is not limited to the specific details shown and described above. Departures may be made from such details within the scope of the accompanying claims without departing from the principles of the invention and without sacrificing its advantages.