US 20160263023A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0263023 A1 KARAVAS et al. (43) Pub. Date: Sep. 15, 2016

(54) PRESERVATIVE FREE PHARMACEUTICAL Publication Classification COMPOSITIONS FOR OPHTHALMC ADMINISTRATION (51) Int. Cl. A619/00 (2006.01) (71) Applicant: PHARMATHEN S.A., Pallini Attikis A 6LX3/55.75 (2006.01) (GR) A647/02 (2006.01) A647/10 (2006.01) (72) Inventors: EVANGELOS KARAVAS, PALLINI A613 L/65 (2006.01) ATTIKIS (GR); EFTHIMIOS KOUTRIS, PALLINIATTIKIS (GR): A 6LX3/5377 (2006.01) VASILIKI SAMARA, PALLINI A63L/382 (2006.01) ATTIKIS (GR): IOANNA KOUTRI, A647/12 (2006.01) PALLINIATTIKIS (GR): ANASTASIA A647/38 (2006.01) KALASKANI, PALLINIATTIKIS A619/08 (2006.01) (GR); ANDREAS KAKOURIS, A647/26 (2006.01) PALLINIATTIKIS (GR); GEORGE (52) U.S. Cl. GOTZAMANIS, PALLINIATTIKIS CPC ...... A61 K9/0048 (2013.01); A61 K9/08 (GR) (2013.01); A61 K3I/55.75 (2013.01); A61 K 47/02 (2013.01); A61 K47/10 (2013.01); A61 K (73) Assignee: PHARMATHEN S.A., 47/26 (2013.01); A61 K3I/5377 (2013.01); PALLINI-ATTIKIS (GR) A61 K3I/382 (2013.01); A61K47/12 (2013.01); A61 K47/38 (2013.01); A61 K (21) Appl. No.: 15/028,685 3 1/165 (2013.01) (22) PCT Fled: Oct. 14, 2014 (57) ABSTRACT (86) PCT NO.: PCT/EP2014/002767 S371 (c)(1), (2) Date: Apr. 11, 2016 The present invention relates to a preservative-free, aqueous Solution in the form of eye drops packed in a container that (30) Foreign Application Priority Data ensures stability of the product, ideal eye drop volume and reduced drop volume variability and provides efficient dis Oct. 15, 2013 (EP) ...... PCT/EP2013/003102 pensing. US 2016/0263023 A1 Sep. 15, 2016

PRESERVATIVE FREE PHARMACEUTICAL tration, there still remains the need in the art for alternative COMPOSITIONS FOR OPHTHALMC formulations providing as well adequate chemical and physi ADMINISTRATION cal characteristics and improved patient compliance. In par ticular, there is a need for formulations that are free from TECHNICAL FIELD OF THE INVENTION preservatives to be provided in a multiple use container and 0001. The present invention relates to aqueous preserva provide efficient dosing of the solution to the patient, without tive-free formulations for ophthalmic administration packed Wastage. in container that ensures physical and chemical stability of the product and provides efficient dispensing. SUMMARY OF THE INVENTION 0010. The present invention aims at developing aqueous BACKROUND OF THE INVENTION pharmaceutical formulations for ophthalmic administration 0002 Ocular administration of drugs is primarily associ that overcome the disadvantages of and provide significant ated with the need to treat ophthalmic diseases. The eye is the improvement over the prior art formulations. most easily accessible site for topical administration of a 0011. It is, therefore, an object of the present invention to medication. Ophthalmic preparations are sterile products provide an efficient ophthalmic product that contains no anti essentially free from foreign particles, Suitably compounded microbial preservatives. Such product is as effective in terms and packaged for instillation into the eye. They are easily of therapy as products available with preservatives. administered by the nurse or the patient himself, they have 0012 Another object of the present invention is to provide quick absorption and effect, less visual and systemic side an ophthalmic product that is stable over time at ambient effects, increased shelf life and better patient compliance. temperature. 0003 Drugs may be delivered to the eye through the appli 0013. A further object of the present invention is to pro cation of four primary modes of administration: Systemic, vide an aqueous pharmaceutical formulation for ophthalmic topical, intravitreal, and periocular. Topical administration is use that effectively addresses issues related to physiological generally considered the preferred route for the administra acceptability by patient. tion of ocular drugs due to its convenience and affordability. 0014. A further approach of the present invention is to Drugs applied in this manner can be in multiple forms, includ provide ophthalmic Solutions that are easily administrable in ing solutions, ointments and Suspensions. drop form. 0004 Drug absorption occurs through corneal and non 0015. In accordance with the above objects of the present corneal pathways. Most non-corneal absorption occurs via invention, eye drops with ideal volume are provided by con the nasolacrimal duct and leads to non-productive systemic trolling Surface tension of the ophthalmic solution and pack uptake, while most drug transported through the cornea is ing the product in container with appropriate design. taken up by the targeted intraocular tissue. Unfortunately, 0016 A further aspect of the present invention is to pro corneal absorption is limited by drainage of the instilled solu vide reduced drop volume variability in order to obtain higher tions, lacrimation, tear turnover, metabolism, tear evapora degree of accuracy and better treatment outcomes. tion, non-productive absorption/adsorption, limited corneal 0017. Other objects and advantages of the present inven area, poor corneal permeability, binding by the lacrimal pro tion will become apparent to those skilled in the artin view of teins, enzymatic degradation. the following detailed description. 0005. The objective of ocular medication delivery is maxi mizing the amount of medication that reaches the ocular site DETAILED DESCRIPTION OF THE INVENTION of action in Sufficient concentration to produce a beneficial 0018 For the purposes of the present invention, a pharma therapeutic effect. This is determined by the dynamics of ceutical composition comprising an active ingredient is con ocular pharmacokinetics: absorption, distribution, metabo sidered to be “stable' if said ingredient degrades less or more lism and excretion. slowly than it does on its own and/or in known pharmaceuti 0006 Aqueous solutions are most commonly used for the cal compositions. eye. They are the least expensive medications and interfere 0019 Antimicrobial preservatives are added to aqueous least with vision. Some commonly used ocular medications preparations that are required to be sterile, Such as in oph are topical anesthetics, mydriatics and cycloplegics, medica thalmic Solutions. The use of preservatives in topical oph tions used to treat glaucoma, anti-infectives, corticosteroids thalmic treatments is ubiquitous for any product that is to be and non-steroidal anti-inflammatory drugs. used more than once by the patient as they prevent any 0007 EP 0999825 B1 discloses atopical ophthalmic com microbes that may enter into the product after its first use from position comprising one or more galactomannan(s) and one allowing those microbes to grow and infect the patient on a or more borate compound(s), wherein the galactomannan and later use of the product. Antimicrobial preservatives are not the borate compound are contained in the composition in found in single use vials of ophthalmic Solutions since they concentrations effective to create a gel or partial gel when the are manufactured aseptically or are sterilised and the products composition is administered to an eye. are used once and the dispenser is thrown away. Although 0008 U.S. Pat. No. 7491383 B2 discloses compositions providing effective biocidal properties with well tolerated comprising a therapeutic component and an efficacy enhanc short-term use at low concentrations, preservatives can cause ing component that enhances the pharmacokinetic disposi serious inflammatory effects on the eye with long-term use in tion of the therapeutic component. The therapeutic compo chronic conditions, such as glaucoma or potentially ocular nent and the efficacy enhancing component may form a allergies. complex. 0020. As the incorporation of preservatives in topical oph 0009. Although each of the patents above represents an thalmic solutions becomes more common, sensitization attempt to provide stable Solutions for ophthalmic adminis toward them is increasing. For example, the salts of benza US 2016/0263023 A1 Sep. 15, 2016

Ikonium have been classified as being moderately allergic 0027 Tonicity refers to the osmotic pressure exerted by whereas mercurial products are strongly allergic. Thimerosal salts in aqueous Solution. An ophthalmic Solution is isotonic may cause ocular delayed hypersensitivity. Chlorhexidine with another solution when the magnitudes of the colligative may cause corneal endothelium damage. Parabens are properties of the Solutions are equal. An ophthalmic Solution capable of producing immunologically mediated, immediate is considered isotonic when its tonicity is equal to that of systemic hyperSensitivity reactions. 0.9% sodium chloride solution (290 mOsm). If the tonicity 0021. As the use of preservative containing eye drops has deviates too far from this value, the pain produced evokes a been implicated in the development or worsening of ocular reflex tearing that washes the drug from the eye. Conse Surface disease, there is a tendency to limit their use by quently, a certaintonicity agent must be added so that the total reducing their concentration as much as possible in eye drops. osmotic pressure is the same as the body fluid. Sodium chlo The present invention provides completely preservative-free ride, mannitol, dextrose, glycerine, potassium chloride are ophthalmic formulations. Such formulations are packed in typical tonicity agents. Isotonicity is desirable and particular containers that enable to deliver preservative-free formula important in intraocular solutions. The present invention pro tions while providing shelf life similar to traditional formu vides isotonic ophthalmic Solutions. lations. The containers of the present invention ensure that 0028 Generally, the tonicity agents bring the osmolality medication is kept germ-free even after multiple uses. of the solutions to a level at or near 210-320 mOsm/Kg. The 0022 Preservative free ophthalmic products are commer ophthalmic compositions of the present invention have an cially available but these are sold as single use vials made by osmolality in the range of 250-300 mOsm/Kg, most prefer using a suitable in a blow-fill-seal process. The user ably in the range of 266-296 mCsm/Kg. takes the plastic vial and tears or cuts the plastic tip, inverts the 0029 Viscosity is the property of resistance to flow in a vial and Squeezes the ophthalmic liquid into the eye. fluid or semifluid. It is an important parameter for ophthalmic 0023. In addition, the use of preservatives is prohibited in compositions. With high viscosity ophthalmic compositions ophthalmic products that are used during eye Surgery because the liquid drip is poor at the nozzle during extraction from the if the preservative contacts the corneal endothelium the cells container, and much of the liquid remains adhering to the area can become damaged causing clouding of the cornea and near the outside of the nozzle after the liquid has been possible loss of vision. dropped. This is undesirable because the remaining liquid can 0024 Patient compliance is greatly increased as the lead to contamination including adhesion of foreign matter, pumps of the present invention permit them to use preserva and as a result, the ophthalmic liquid composition can poten tive-free eye drops without worrying about the potential side tially be dropped through a contaminated nozzle at the time of effects caused by some preservatives and the related short the next use. Particularly in the case of eye drop compositions, and long-term consequences, such as pain or discomfort, excessively poor liquid drip produces a difference in the drop foreign body sensation, stinging or burning, dry eye sensa Volume, leading to the problem of variation in drug dosage. tion, ocular Surface breakdown. 0030 The ophthalmic compositions of the present inven 0025. In addition we have found that careful selection of tion have viscosity of less than 200 cp at 25°C., more pref certain physical properties of the ophthalmic solution and erably the viscosity is less than 150cP at 25° C. also the design of the tip of the container produce a highly 0031. The preferred compositions of the present invention accurate drop size with low variability of drop volume are free of viscosity-increasing agents examples of viscosity between each drop dispensed. increasing agents that are absent include one or more of the following: alginic acid, carrageenan, chitosan, gelatin, guar Ophthalmic Solutions gum, maltitol, maltodetrin, Sucrose, Xanthan gum, calcium silicate and sorbitol. 0026. The solutions of the present invention are sterile and free from any microbial preservative. Some common oph 0032) Ophthalmic preparations should be formulated at a thalmic drugs suitable for use in this invention include, but are pH equivalent to the tear fluid value of 7.4. Practically, this not limited to, chloramphenicol, timolol, dorzolamide, tra seldom is achieved as the large majority of active ingredients voprost, bimatoprost, latanoprost, prednisolone, levobunolol. used in ophthalmology are salts of weak bases and are most levofloxacin, moxifloxacin, dexamethasone, apraclonidine, stable at an acid pH. Optimum pH adjustment generally bromfenac, epinastine, loteprednol, pegaptainib, predniso requires a compromise on the part of the formulator. It is lone, pranoprofen, ranibiZumab, rimexolone, trafluprost, thi generally accepted that a low pH (acid) perse necessarily will omersal, betaxolol, brimonidine, carteolol, pilocarpine, brin not cause stinging or discomfort on instillation. If the overall Zolamide, apraclonidine, atropine, azelastine, bepotastine, pH of the tears, after instillation, reverts rapidly to pH 7.4, betaxolol, bromfenac, ciprofloxacin, diclofenac, emedastine, discomfort is minimal. On the other hand, if the buffer capac epinastine, flurbiprofen, gentamycin, gramicidin, framycetin ity is sufficient to resist adjustment by tear fluid and the Sulphate, cetrimide, hamamelis water, naphazoline, homatro overall eye pH remains acid for an appreciable period of time, pine, ketorolac trometamol, ketotifen fumarate, levobunolol. then stinging and discomfort may result. Consequently, lodoxamide trometamol, moxifloxacin, naphazoline, phe buffer capacity should be adequate for stability but mini niramine maleate, nedocromil sodium, ofloxacin, olopata mized, so far as possible, to allow the overall pH of the tear dine, tetracaine, tetrahydrozoline, tobramycin, Xylometazo fluid to be disrupted only momentarily. A preferred range of line, antazoline and combinations such as travoprost/timolol. pH therefore must be selected according to the active ingre dorzolamide/timolol, bimatoprost/timolol, brimonidine/ dient used. timolol, latanoprost/timolol, brinzolamide/timolol. Addition 0033 Preferred compositions are prepared using a buffer ally some ophthalmic solutions have no active ingredient as ing system that maintains the composition at a pH of about 5 Such but act as a lubricant and are commonly called artificial to a pH of about 8, most preferably 5.5-7.5. Suitable buffering tears or hypromelosse eye drops. agents include, but are not limited to, dibasic sodium phos US 2016/0263023 A1 Sep. 15, 2016 phate, monobasic sodium phosphate, hydrochloric acid, of the drug due to systemic absorption can be greatly influ Sodium hydroxide, Sodium hydrogen carbonate. enced by the volume instilled. 0034 Surface tension.The actual formation of the drop at 0043. Several physical factors of the solution used will be the orifice of the tip depends primarily on the surface tension responsible for variation in drop size and these are viscosity of the Solution, assuming the tip is identical. According to and Surface tension. In addition the other factors are those Tate's law: W-mg 2 tyr, where W is the weight of the drop, associated with the container and the especially the dispens m is the mass of the drop, g is the acceleration of gravity, Y is ing tip of the container—assuming that the other factors of the the surface tension of the liquid and r is the radius of the tip. Solution are constant Such as Viscosity and Surface tension. This equation shows that a decrease in the Surface tension will The inner diameter and the width of the flat end of the dropper reduce the drop weight. The surface tension is affected by the tip and the dispensing angle have been found the most impor excipients used in formulations. The present invention pro tant. The dispensing angle can be fixed—or at least recom vides ophthalmic solutions with lower surface tension. Sur mended to the patient. Assessment of the repeatability of face tension is reduced by the addition of surfactants. achieving the correct drop size and of any factors likely to 0035. Preferred surfactants are nonionic surfactants such cause increased variation is therefore of great clinical impor as the sorbitan ether esters of oleic acid (polysorbate or tance. tween R.20 and 80), macrogol glycerol hydroxystearate (cre mophor RH-40R), glyceryl monooleate, polyoxyethylene Drop Size Variability Stearates, triethylcitrate. 0036. The concentration of surfactant is preferably at a 0044) Drop size variability of the preservative free oph range of from 0.01% to 2% by weight, more preferably 0.01% thalmic Solutions is reduced in containers of the present to 1% by weight and most preferably 0.01% to 0.5% by invention. The drop volume is in the range of 22-31 most weight. preferably 22.7-30.7 ul when the tip of the nozzle is at 45°, 0037. The compositions of the present invention may also when using ophthalmic Solutions described herein. comprise other common excipients used in ophthalmic prepa 0045. The variability between each drop dispensed is +5ul rations such as antioxidants, salts and/or Surfactants. or expressed as +0.1 gtt. Ideally the drop variability can be 0038 Common excipients used in ophthalmic composi expressed as +15%, ideally +10% due to some variability id tions are for example borates, mannitol, phosphoric acid, drop size according to the formulation. ethyl oleate, propylene glycol, lecithin. Tip Drop Size 0046) Several dropper tip designs can be distinguished: 0039. In the Pharmacy field the term “drop” (as a unit) has the simplest design is a nozzle with a small opening for the been standardised to exactly 0.05 ml (so 20 drops equals 1 ml) passage of the liquid; dropper tips with a straight elongated which abbreviated as “gtt' (org.tts for the plural) coming from cylindrical channel of uniform cross-section and narrower gutta, the latin word for drop. Preferably the drop dispensed is inner aperture; tips with a conical outward channel below a 0.3 to 1.1 gtt, preferably 0.4 to 1.0 gtt and ideally 0.45 to 0.9 cylindrical recess channel. Changes in dimension of eye gtt. dropper tip can alter drop Volumes markedly. 0040. The average volume of a human tear is 7 ul. The 0047 Smaller eye drops are obtained with a tip having the conjunctival sac is capable of holding 20-30 ul of fluid with inner diameter that is approximately one-half of the size of the out overflowing onto the cheek; however the average drop outer diameter. size of commercial topical medications for the eye is around 0048. The flow of the liquid through the dropper tip and 39 ul. The excess fluid runs to the cheeks or drains to the the drop size depends on the inner aperture and outer orifice naso-lacrimal system, where it will be absorbed systemically diameter. Preferably there is a constant inner diameter of the without first-pass metabolism by liver, and might cause dropper tip orifice. In Such a system the eye drop size unwanted side effects. One way to overcome this problem is increases linearly with the outer diameter. Dropper tips of the to reduce the size of the drop. In order to obtain eye drops with present invention control the size of the drops by control of ideal Volume, Small-dimension dropper tips are necessary. the inner diameter relative to the outer diameter. 0041. The angle at which the dropper bottle is held is 0049. To provide the drop size and drop size variability for another factor which influences the drop size. Dispensing the preservative free solution described in the present inven drops from a droppertip at an angle of 45° from the horizontal tion we have found that ideally the dispensing tip should have significantly decreases the average drop Volume. As a result the following dimensions: the ratio of the inner to the outer of gravity, tilting from a vertical position to 45° from the diameter of the dispensing tip is from 1:1 to 1:6, preferably horizontal reduces the perimeter of the outer orifice of the from 1:1 to 1:4, most preferably from 1:1 to 1:2. dropper tip, at which a drop is formed, and Smaller drops 0050. The inner diameter of the dispensing tip is more than would be expected. The weight of a drop is proportional to the 0.3 mm and less than 2 mm; the outer diameter of the dis radius of the dropper tip according to Tate's law; therefore, a pensing tip is more than 1 mm and less than 4 mm, wherein decrease in the drop weight can be obtained when changing the outer diameter is the diameter the tip of the nozzle at the the angle from 90° to 45°. point the drop exits the nozzle and the inner diameter is the 0042. A serious problem related to the use of eye drops diameter of the nozzle at the point the drop exits the nozzle that are free from preservatives is the considerable degree of and to which internally the ophthalmic composition moves imprecision in the dose administered. This is due to the impre from the reservoir to the tip. cise way in which the dosing tip is formed when plastic vial is 0051. Therefore, we present as a feature of the present torn or cut to remove the tip of the vial as described below. invention a multi-use ophthalmic product comprising a con This may be a cause for concern since the pharmacological tainer with an integral bacterial protection system and which effect of a compound and the related adverse systemic effects has a dispensing tip, wherein the ratio of the inner to the outer US 2016/0263023 A1 Sep. 15, 2016

diameter of the dispensing tip is from 1:1 to 1:6, and the ensure the microbiological safety of the non-preserved prod container having an ophthalmic composition that is dispensed uct, Such containers are equipped with bacteria protection from the tip into the eye of a patient wherein the ophthalmic mechanisms. composition is a preservative-free aqueous solution and con tains pharmaceutically acceptable excipients selected so as to 0059. Today a range of technical solutions are available to provide the following physical parameters to the solution: overcome this issue and provide bacterial protection mecha 0052 a. viscosity of less than 200 cFat 25°C. nisms. The highest risk of contamination obviously comes 0053 b. surface tension of less than 22 mN/m and more from the tip from which the solution exits the container, than 10 mN/m at 25° C. because it may come in contact with skin and mucosa as well wherein the combination of the dispensing tip and the prop as with infected body fluids. Solutions to prevent contamina erties of the composition produce a dispensed drop Volume of tion via the tip divide into two distinct groups: between 22 ul and 31 Jul when the tip is at 45°. 0060) 1. Containers having "oligodynamic effect have an open tip release ions into the formulation that Containers are toxic to bacteria. Examples include the use of 0054) A number of different containers for ophthalmic wire in the tip of the actuator, a silver coated spring and Solutions exist ranging from single use to multiple-use. In the ball. These components release silver ions into the for present invention the containers used are multiple-use con mulation, which is a time dependent process. The sys tainers. This means that the device contains more than one tem is able to keep down between long dose of ophthalmic Solution. Single use products are typically dosing intervals, even when the tip is immersed into simple blow-fill-seal containers, such as single use glass/ bacterial contaminated fluid. Silver ions are widely used plastic ampoules, vials where the tip is removed and the for their properties and even when used for content Squeezed into the eye and the container is then dis wound dressings, it is safe and no adverse effects are carded. Due to the tip being torn of shorn away then the drop attributed to this treatment. One general limitation of Volume is highly variable and the quantity of Solution pro course must be considered: the silverions may react with vided is normally largely in excess of that needed. This leads certain ions in the formulation and may form precipi to a lot of wastage in the Solution and packaging. This type of tates—such as with chloride ions. product has one major advantage; it is sterile and used only 0061 2. Containers that use a “mechanical effect” to once, therefore, a preservative is not required. prevent contamination. Typically this is called “tip seal 0055. The container volume of the present invention is technology' and is a simple spring loaded valve located preferably from 5 to 15 ml, most preferably from 5 to 10 ml. directly below the opening of the tip orifice that does not 0056 Preferably the containers are made from glass or allow any microbes to migrate from any Surfaces or plastic materials (e.g. polyethylene, polypropylene, PET). contacted liquids into the system; the orifice is sealed Glass bottles are less prone to give interactions and will give under resting conditions. The tip seal keeps the system good protection to the formulation even during storage inter closed until a defined pressure is reached then the system vals. The disadvantages that glass bottles may have are the will open and the formulation is forced through the higher weight, the risk to break when dropped, the higher orifice with a higher pressure than needed to open the costs. On the other hand, bottles made of plastic materials valve. When the pressure drops at the end of the actua offer increased patient compliance in the case of ophthalmic tion the tip seal will immediately close the orifice with an products as the patient needs only to squeeze the bottle to outward movement. So no backflow of potentially con dispense the product. taminated medication or other liquid is possible. 0057 Multiple-use containers are widely used and they have the disadvantage in that a preservative system is 0062. Additionally to protect the integrity of the solution required. This is due to the danger of bacteria entering into the Such devices may also have a system to prevent bacteria container and contaminating the solution. There are two path entering when the system vents. So after use a negative pres ways for microorganisms to enter the container: a) via the Sure develops inside the container and air may flow back into orifice created at the tip and any remaining liquid attached to the container which may carry air born bacteria. Integrity is it coming into contact with infected tears or skin and b) via the achieved by a "mechanical effect” and may be one or more of venting air where the Solution dispensed from the container is the following: replaced by ambient air. 0.063 1. Collapsible internal bag to contain the solution. The use of an internal collapsible bag to contain the Bacterial Protection Mechanism systems avoids any negative pressure developing. 0058. In preserved formulations the added preservative 0064. 2. Filters, these simply filter the air and trap any controls microbial growth and no additional measures need to airborn bacteria be taken to prevent microbial occupation via the orifice or venting air of the container. If the formulation does not con 0065 3. Unvented containers—these are containers that tain preservatives, the device must be able to keep microor do not allow any air to come back into the container at ganisms out of the containerto prevent bacteria colonising the all. Negative pressure continues to build throughout the Solution inside and requires one or more bacterial protection use of the product without affecting the performance of mechanisms. Newly developed multiple use containers are the container to deliver the solution. known that do not require a preservative system since they 0066. The following examples illustrate preferred prevent entry of bacteria into the container due to their special embodiments in accordance with the present invention with construction and inclusion of germ reducing components. To out limiting the scope or spirit of the invention. US 2016/0263023 A1 Sep. 15, 2016

EXAMPLES -continued

Example 1 Ingredients % Wiw

0067 NaOH. O.1N qs Sodium Citrate O.294 Ingredients % Wiw Natrosol HX 250 0.570 Water for injection C.S. Travoprost O.004 Cremophor RH-40 O.200 NaCl O.3SO Propylene glycol 0.750 O.300 0080. The manufacturing process as followed for the Mannitol O.300 preparation of Composition 3 consists of the following steps: NaOHAHCI q.S. pH = 6.0 water for injection C.S. Preparation of Solution A 0068. The manufacturing process as followed for the 0081. Adding.Mannitol into purified water (which rep preparation of Composition 1 consists of the following steps: resents about 60% of the total solution volume) and dissolving; 0069. Adding 80% of the total volume of purified water in a clean vessel of appropriate size; 0082. Adding API and dissolving: 0070 Adding Propylene glycol and dissolving: 0.083. Adding Sodium citrate and dissolving: 0071. Adding.Mannitol, Boric acid and dissolving: 0084 Adjusting pH to 5.65 by adding the necessary amount of NaOH 0.1 N 0072 AddingCremophor RH-40 and stirring till com plete dissolution; I0085 Sterilizing SOLUTION A by filtration through 0.2 um filter. 0073. Adding NaCl; 0074 Adjusting solution pH to 6 using NaOH or HCl; Preparation of Solution B 0075 Adding API and stirring until complete API dis Solution; I0086. Adding Natrosol in purified water (which repre sents about 35% of the total solution volume) and dis 0076 Adjusting solution volume. Solving; Example 2 0.087 Autoclaving SOLUTION B for 30 min at 121°C. 0.077 Mixing of Solution A and Solution B I0088 Mixing cool SOLUTION A and cool SOLU Ingredients % Wiw TION B; Travoprost O.004 0089 Adjusting solution volume using water for injec Timolol maleate O.68O Cremophor RH-40 O.200 tion. NaCl O.3SO Propylene glycol 0.750 Boric acid O.300 Example 4 Mannitol O.300 NaOHAHCI q.S. pH = 6.0 0090 Water for injection C.S.

0078 Composition 2 was prepared with the same manu Ingredients % Wiw facturing process as in Example 1. Dorzolamide hydrochloride 2.226 Timolol maleate O.683 Example 3 Mannitol 1600 NaOH. O.1N C.S. 0079 Sodium Citrate O.294 Natrosol HX 250 O.S8O Water for injection C.S. Ingredients % ww. Dorzolamide hydrochloride 2.226 Mannitol 2. SOO 0091 Composition 4 was prepared with the same manu facturing process as in Example 3. US 2016/0263023 A1 Sep. 15, 2016

Drop Sizes Achieved 0092

SURFACE OSMOLALITY SPECIFIC TENSION Drop Volume COMPOSITIONS PH VICOSITY (cP) (mosm/Kg) GRAVITY (mN/m) (LL) Travoprost 6.30 O.9-1.1 28O 1.018 12.00-13.OO 22.7-29.3 Travoprost- 6.30 O.9-1.1 286 1.007 12.00-13.OO 22.7-29.3 Timolol Dorzolamide 5.67 124-138 285 1.020 19.34 307-413 Dorzolamide- S.66 135-1SO 276 1.020 19.21 30.2-39.8 Timolol Timolol 7.03 O.9-1.1 296 1.016 2011 28.3-38.8 Chloramphenicol 7.29 O.9-1.1 281 1.011 21.22 29.6-405 Bimatoprost 7.31 O.9-1.1 287 1.007 17.11 26.3-34.8

0093. The pH, viscosity, osmolality, specific gravity, Sur 0102 The container used for the rest of compositions uses face tension and drop Volume of compositions prepared the mechanical tip-seal technology to prevent bacterial con according to the present invention were measured via certi tamination. fied methods. 0103) While the present invention has been described with 0094. The pH of the compositions was measured accord respect to the particular embodiments, it will be apparent to ing to European pharmacopoeia requirements (Potentiomet those skilled in the art that various changes and modifications ric determination of pH; 01/2005:20203). may be made in the invention without departing from the 0095. The viscosity of the compositions was measured spirit and scope thereof, as defined in the appended claims. according to European pharmacopoeia requirements (Capil 1. A multi-use ophthalmic product comprising a container lary viscometer method; 01/2005:20209 or Rotating viscom with an integral bacterial protection system and a dispensing eter method; 01/2005:20210). tip, wherein the ratio of the inner to the outer diameter of the 0096. The osmolality of the compositions was measured dispensing tip is from 1:1 to 1:6, and the container having an according to European pharmacopoeia requirements (OSmo ophthalmic composition that is dispensed from the tip into the lality: 01/2005:20235). eye of a patient, wherein the ophthalmic composition is a 0097. The specific gravity of the compositions was mea preservative-free aqueous solution and contains pharmaceu Sured according to US pharmacopoeia requirements (Specific tically acceptable excipients selected so as to provide the gravity; USP29/841). following physical parameters to the Solution: 0098. The surface tension of the compositions was mea a) viscosity of less than 200 cpat 25° C. as measured by sured via Kruss DSAIS easy drop tensiometer. Is there an EU European pharmacopoeia requirements (Capillary vis P method? cometer method; 01/2005:20209) 0099. The drop volume of the compositions was measured b) surface tension of less than 22 mN/m and more than 10 by measuring the weight of individual drops using an analyti mN/m at 25° C. cal balance and then dividing by the Solution density. wherein the combination of the dispensing tip and the prop 0100. The results of drop volume incorporate measure erties of the composition produce a dispensed drop Volume of ments both from vertical position and from 45° angle. The between 22 Jul and 31 Jul when the tip is at 45° and the Smallest average drop Volume was achieved at an angle of 45° variability between each drop dispensed is +7 ul. from the horizontal. The drop volume for each product was 2. An ophthalmic product according to claim 1, wherein the tested and found to vary by not more than +5uL. ophthalmic composition has an active ingredient selected from chloramphenicol, timolol, dorZolamide, travoprost, TABLE 2 bimatoprost and combinations thereof Such as travoprost/ Surface tension measurements timolol, dorzolamide?timolol. PRESERVATIVE FREE PRODUCTS 3. An ophthalmic product according to claim 1, wherein the pH value of the composition is between 5.5 and 7.5 as mea SURFACE TENSION DROPVOLUME Sured by European pharmacopoeia requirements (Potentio COMPOSITIONS (mN/m) (II) metric determination of pH; 01/2005:20203). Dorzolamide 1139-1145 22.47-22.58 4. An ophthalmic product according to claim 1, wherein it Dorzolamide, Timolol 11.09-11.27 21.07-21.21 Timolol 13.08-13.74 21.54-23.85 has an osmolality value of 250 to 300 mOsm/Kg, most pref Chloramphenicol 15.75-16.04 34:28-35.20 erably from 266 to 296 mCsm/Kg European pharmacopoeia Bimatoprost 13.92-1424 23.91-26.13 requirements (Osmolality: 01/2005:20235). 5. An ophthalmic product according to claim 1, wherein the 0101 The container used for the compositions comprising variability between each drop dispensed is +5ul. Travoprost and Travoprost/Timolol ensures microbiological 6. An ophthalmic product according to claim 1, wherein it safety by incorporating germ-reducing components contain is in the form of eye drops. ing oligodynamically active silver. k k k k k