Ophthalmic pharmaceutical compositions, their preparation and use

Abstract

The present invention relates to an ophthalmic composition in the form of an oil-in-water (O / W) emulsion, which mainly contains propylene glycol and sodium hyaluronate. The present invention also relates to a method for preparing and using an artificial tear composition.

Description

[Technical Field]

[0001] The present invention relates to ophthalmic pharmaceutical compositions, specifically ophthalmic compositions in the form of oil-in-water (O / W) emulsions. More specifically, the present invention relates to nanoemulsions made with propylene glycol. The present invention also relates to ophthalmic compositions that do not generate high viscosity due to the emulsification process and that do not contain preservatives in their manufacturing process. The present invention also relates to compositions that not only lubricate the ocular surface but also prevent evaporation of tears formed during administration, due to their preparation process and tear stabilization. Similarly, the present invention relates to preservative-free ophthalmic compositions and methods of administering them. [Background technology]

[0002] Various artificial tear formulations are known to treat tear film disorders, which generally result from an eye disorder that results in the inability of the eye to produce adequate amounts of tears or to maintain the proper balance of tear components on the mucous membrane.

[0003] Natural tears consist of a lipid phase (neutral lipids, fatty acids, cholesterol, phospholipids, glycolipids), a serous phase [proteins, electrolytes (sodium, magnesium, calcium, chloride, bicarbonate)], and a mucin phase (proteins, hydrocarbons, enzymes).

[0004] On the other hand, artificial tears are mainly composed of a fatty phase and an aqueous phase (lubricant, electrolyte, glycerin, polymer).

[0005] In this context, existing artificial tear compositions designed to reduce or alleviate moderate to severe dry eye include polymers that mimic the mucous, aqueous, and / or lipid layers to maintain film stability and reduce rapid evaporation ( Horn et al., 2017 ).

[0006] However, due to effective protective mechanisms to ensure normal ocular function, the intraocular bioavailability of topically administered drugs is very limited. Such barriers are difficult to overcome with drop-type pharmaceuticals. Another challenge to consider is achieving optimal drug concentrations at the site of action (Souto et al., 2010).

[0007] Ophthalmic drug delivery has become a key challenge to improve the efficacy of topical treatments and overcome ocular disorders. Most successful delivery systems provide long-term retention on the ocular surface, improving the bioavailability of drugs in the anterior segment of the eye (Rawas-Qalaji and Williams, 2012).

[0008] Over the past few decades, various delivery systems for drugs, such as liposomes, nanoemulsions, microemulsions, nanoparticles, and dendrimers, have become new strategies to improve the bioavailability of ophthalmic drugs ( Souto et al., 2010 ).

[0009] In general, nanoparticle technology offers various advantages, such as solubilization of hydrophobic and poorly soluble drugs, improving their bioavailability and pharmacokinetic properties, as well as protecting drugs from physical, chemical, and biological degradation. Furthermore, the submicron size of these molecular systems allows for efficient transport and crossing of biological barriers, such as the eye, enabling precise drug delivery to the target site.

[0010] In this regard, nanometric emulsions, also referred to in the literature as miniemulsions, ultrafine emulsions, or submicron emulsions, are emulsions whose droplets are nanometers in size (less than 100 nm).

[0011] Although the appearance of these two types of colloidal dispersions is similar, it is important to note that microemulsions are thermodynamically stable molecular systems (i.e., they form spontaneously), whereas nanoemulsions are thermodynamically unstable and require energy for their formation.

[0012] The energy required can be supplied from an external source (dispersion or high-energy methods) or an internal source (condensation or low-energy methods). High-energy emulsion methods use mechanical devices that generate high disruptive forces to break down the oil and water phases to produce small droplets. The most commonly used devices for producing nanoemulsions include rotor / stator, high-pressure, and ultrasonic methods.

[0013] In recent years, high-energy emulsification methods that have been actively developed include microfluidic and biofilm methods, which provide practically monodisperse droplets and consume relatively low energy.

[0014] For example, International Application No. WO / 2018 / 071619 describes artificial tears and contact lens storage compositions containing one or more nonionic surfactants, viscosity modifiers, polyols, and electrolytes such as sodium chloride. This document points out the "moisture trap" or "moisture lock" effect, which is a simple mechanical effect resulting from the interaction of highly viscous (300 to 400 cps) droplets when applied. However, the use of highly viscous droplets can temporarily blur the user's vision.

[0015] Additionally, U.S. Patent Application No. US 2016 / 0101050 describes an ophthalmic nanoemulsion that can increase the solubility of an active substance such as cyclosporine while also ensuring greater stability of the overall composition, although the particle size distribution is not uniform overall compared to other compositions.

[0016] Meanwhile, Chinese Patent Application No. CN 101391111 discloses a contact lens care solution and moisturizing eye drops that use (water-soluble) polyoxylated castor oil and a disinfectant.

[0017] In view of these circumstances, there is a need for artificial tear-type compositions that promote lubrication of the ocular surface while avoiding all of the aforementioned drawbacks. There is also a need for compositions that maintain the integrity and effectiveness of contact lenses. There is also a need for preservative-free artificial tear-type compositions. Summary of the Invention [Problem to be solved by the invention]

[0018] It is therefore an object of the present invention to provide an ophthalmic composition in the form of a nanoemulsion consisting of an organic compound consisting of a diol, a stabilizing polymer, preferably a glycosaminoglycan type polymer, a fatty acid or a phospholipid, and other pharmaceutically acceptable excipients.

[0019] An additional object of the present invention is to provide an artificial tear-type composition that provides relief from non-bacterial conjunctivitis without damaging contact lenses.

[0020] Another object of the present invention is to provide an ophthalmic composition in which the use of sodium hyaluronate does not result in high viscosity.

[0021] Another object of the present invention is to provide an ophthalmic composition that stabilizes tears, thereby lubricating the ocular surface and preventing evaporation of tears formed during administration.

[0022] Another object of the present invention is to provide a method for preparing an ophthalmic composition.

[0023] Another object of the present invention is to provide a system for containing and administering a preservative-free ophthalmic composition. [Means for solving the problem]

[0024] Another preferred form for carrying out the invention involves the diol organic compound, namely propylene glycol.

[0025] In yet another embodiment for carrying out the invention, the glycosaminoglycan type polymer is preferably sodium hyaluronate.

[0026] In another preferred embodiment, the phospholipid consists of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and castor oil.

[0027] In a preferred embodiment of the invention, sodium hyaluronate is subjected to a high-impact emulsification process, which fragments the polymer into dispersed monomers in the formulation, allowing the active ingredients to be more effectively delivered to the corneal epithelium and contribute to healing. [Brief explanation of the drawings]

[0028] [Figure 1] 1A and 1B are electron microscope images comparing the commercially available SYSTANE BALANCE® (1A) with the ophthalmic composition of the present invention (1B). [Figure 2] 2A and 2B are graphs comparing the particle size distribution of the commercially available SYSTANE BALANCE® (2A) and the ophthalmic composition of the present invention (2B). [Figure 3] 3A and 3B are graphs comparing the zeta potential of the commercially available SYSTANE BALANCE® (3A) and the ophthalmic composition of the present invention (3B). [Figure 4] 4A and 4B are graphs comparing the electrophoretic mobility of the commercially available SYSTANE BALANCE® (4A) and the ophthalmic composition of the present invention (4B). [Figure 5] 5A and 5B are comparative graphs of homogeneity testing of the commercially available SYSTANE BALANCE® (5A) and the ophthalmic composition of the present invention (FIG. 5B). [Figure 6] Figure 6 is a diameter tolerance graph for a Type I contact lens [a soft contact lens replaced monthly, composed of 67% polymer (Rotraficon B) and 33% water], diopter 1.0. [Figure 7]FIG. 7 is a thickness tolerance graph for a Type I contact lens, diopter 1.0. [Figure 8] FIG. 8 is a diameter tolerance graph for a Type I contact lens, diopter 6.0. [Figure 9] Figure 9 is a tolerance graph of the ultraviolet transmittance of a type IV contact lens [a soft contact lens replaced every 15 days, composed of 42% polymer (etafilcon) and 58% water], diopter 6.0. [Figure 10] FIG. 10 is a tolerance graph for a type IV contact lens, diopter 6.0. [Figure 11] FIG. 11 is a schematic diagram showing the mechanism of action or function of the containers that constitute the system of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0029] The details of the present invention are described in the accompanying drawings, which illustrate some, but not all, of its advantages. Because various modes for implementing the invention can be realized in many different ways, the present invention should not be construed as limited to the embodiments set forth herein. Rather, these exemplary embodiments are provided so that the present invention will be comprehensive and complete, and will fully convey the scope of the present invention to those skilled in the art. For example, unless otherwise specified, references to first, second, etc. should not be construed as implying a particular order. As used in this specification and the appended claims, the indefinite and definite articles un, uno, una, el, and la are intended to include the plural reference unless the context clearly dictates otherwise.

[0030] Aspects of the present invention preferably refer to oil-in-water (O / W) nanoemulsion ophthalmic compositions that are evidently administered by eye drop.

[0031] As used herein, the term "composition" is intended to include any product produced directly or indirectly by combining specified compounds in specified amounts and combinations.

[0032] Thus, the ophthalmic composition according to one embodiment of the invention is an isotonic, sterile, homogeneous nanoemulsion containing a polyol such as propylene glycol, polyethylene glycol 300, or sorbitol.

[0033] In a preferred embodiment, the compositions of the present invention contain propylene glycol, preferably at a concentration of 0.1% to 0.6%.

[0034] In another embodiment of the invention, the ophthalmic composition may include stable polymers of the glycosaminoglycan type, such as guar gum, gellan gum, hydroxypropylmethylcellulose, sodium hyaluronate, hydroxyethylcellulose, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, fatty acids and other pharmaceutically acceptable excipients.

[0035] In a preferred embodiment, the stabilizing polymer is sodium hyaluronate. In a preferred embodiment, the fatty acid or phospholipid is DPPC (1,2-dipalmitol-sn-glycero-3-phosphocholine), DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), or DEPC (1,2-dierythroyl-sn-glycero-3-phosphatidylcholine). These are not particularly limited, and the fatty acid used is 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC) and castor oil.

[0036] In the present invention, propylene glycol is a colorless, tasteless, odorless organic compound (alcohol, more precisely diol) that promotes lubrication on the ocular surface, stabilizes tears, and reduces evaporation of the tear film.

[0037] DMPC is a type of phospholipid (fatty acid) and is an amphiphilic molecule that forms the lipid bilayer structure of cell membranes.

[0038] Castor oil acts as a cosolvent, incorporating surfactants into the nanoemulsion, as well as incorporating lipid compounds in the formulation, such as fatty acids, into the system (or emulsion), and this component constitutes the oil phase of the oil-in-water (O / W) nanoemulsions of the present invention.

[0039] The ophthalmic composition in the most preferred embodiment for carrying out the invention can be understood as follows. Propylene glycol 0.1 to 0.6% Boric acid 0.01 to 0.1% Sodium borate decahydrate 0.01 to 0.5% Dimyristoylphosphatidylcholine (DMPC) 0.001 to 0.01% Sodium edetate dihydrate 0.01 to 0.1% Sodium hyaluronate 0.1 to 0.5% Castor oil 1.0 to 5.0% Polysorbate 80 0.2 to 4.0% Glycerin 0.5 to 2.2% Water for injection manufacturing grade (appropriate amount)

[0040] In the present invention, to obtain an emulsion, the mixture of the aforementioned components is homogenized by a physical method (high-energy emulsion method).

[0041] In another aspect of the present invention, one of the main characteristics of an O / W emulsion with regard to the stability and maintenance of its physicochemical properties is the particle size of the oil dispersed in the medium, and according to techniques known to experts in this field, the most commonly used technique for determining this is dynamic light scattering, which determines the correlation of particle size with particle fluctuations.

[0042] Thus, in a preferred embodiment of the invention, the micelles formed by the fatty acids or phospholipids have a particle size distribution ranging from about 30 nm to about 260 nm, more preferably from about 32 nm to about 255 nm. In a more preferred embodiment, the compositions of the present invention have a particle size distribution ranging from about 82.5 nm to about 92.5 nm.

[0043] Another aspect of the present invention is that, in addition to the function of artificial tears, the inventors have discovered that the formulation has a completely unexpected technical first effect: the composition of the present invention not only stabilizes the tear film and lubricates the ocular surface, but also prevents evaporation, thereby preventing blurred vision. This is achieved by the migration of not only the components but also particles or micelles composed of castor oil and DMPC, which are incorporated into the lipophilic layer of natural tears.

[0044] The inventors of the present invention have made the surprising discovery that high-impact emulsification of sodium hyaluronate in ophthalmic compositions results in polymer fragmentation of the monomers dispersed in the formulation, allowing the active ingredient to be more effectively transferred to the corneal epithelium and promoting its recovery.

[0045] In this sense, hyaluronic acid sodium salt is incorporated into emulsions to ensure firmness and viscosity, thanks to its polymeric structure consisting of repeating disaccharide units of N-acetylglucosamine and D-glucuronic acid linked by 1-4 glycosidic bonds.

[0046] In the manufacturing process of the compositions of the present invention, the shear and pressure generated in a three-cycle mechanical emulsification process at pressures of 10,000 psi to 30,000 psi fragments the long-chain sodium hyaluronate into smaller chains.

[0047] In another embodiment of the invention, a method for producing an ophthalmic composition is provided. The manufacturing process was developed taking into consideration the emulsion formulation, the properties of the ingredients, and the method of administration (ophthalmic). The process aims to obtain a stable and homogeneous emulsion.

[0048] Based on the preferred method of administration, the characteristics of the developed formulation, and the type of primary packaging, a sterile product is required, but it should be noted that the product may be amenable to terminal sterilization, which includes product sterilization by filtration, with the filtered product placed in a sterile container and seal system in a sterile environment.

[0049] In one preferred embodiment, the formulation process is carried out in a stainless steel tank equipped with a stainless steel propeller for agitation.

[0050] More preferably, the process described in this application consists mainly of two compounding steps.

[0051] The first step in the formulation process involves identifying a compounding tank and adding 60% to 65% injection-grade water at a temperature of 20°C to 30°C. The tank is constantly agitated, and the following ingredients are added while maintaining constant agitation and temperature ranges: polysorbate 80, dimyristyl phosphatidylcholine (DMPC), boric acid, sodium borate decahydrate, disodium edetate dihydrate, glycerin, propylene glycol, sodium hyaluronate, and finally castor oil, which is the oily phase or emulsion (O / W) of the system.

[0052] In this regard, the oil-in-water mixture is made up to a predetermined volume or capacity with the necessary water-for-injection grade water, and the mixture is homogenized before emulsification.

[0053] In the second stage, this oil-water mixture is subjected to a mechanical emulsification process, which must be carried out under controlled pressure and temperature.

[0054] In a preferred embodiment, the addition and temperature conditions for the formulation process may be as follows:

[0055] [Table 1]

[0056] According to the present invention, castor oil not only serves as a cosolvent for incorporating 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC or dimyristylphosphatidylcholine) into the formulation, but also represents the oily (or internal) phase of the emulsion in the formulation, since this excipient is a fatty acid, and represents 1% of the total concentration of ingredients in the artificial tear composition.

[0057] In steps 10 to 12, this 1.0% castor oil is incorporated into the formulation to form a mixture of oily and aqueous phases, which undergoes a 60-minute homogenization step and finally undergoes three cycles of mechanical emulsification at pressures ranging from 10,000 psi to 30,000 psi to ensure homogenization of both emulsion phases.

[0058] During formulation process development, ensure that the agitation speed is between 78 and 840 rpm. This ensures that the water flow generated in the tank during solubilization of the ingredients does not create turbulence that could trap air in the emulsion. For the same reason, attention must be paid to the homogenization speed before the emulsification step in the equipment.

[0059] Finally, the sterilization step is carried out by filtration, preferably using two sterilizing membranes made of polyethylsulfone with a pore size of 0.2 μm. The filters used are subjected to a membrane integrity test as a control.

[0060] In a preferred embodiment, the specified compounds are contained in the appropriate proportions, taking into consideration the stirring speed of 78 to 840 rpm, the solubilization time and the product temperature.

[0061] [Table 2]

[0062] In another aspect of the present invention, a system is provided for containing and administering a preservative-free artificial tear composition.

[0063] The system contains an artificial tear composition that promotes lubrication of the ocular surface. It consists of a low-density polyethylene container with a modular high-density polyethylene locking mechanism equipped with a silicone and low-density polyethylene valve. It is compatible with a wide range of viscosities, is easy to use, and requires little force to activate the mechanism.

[0064] The function of this multi-dose container is to adjust the amount of product inside the container, prevent the intrusion of air and contaminants from the outside using a check valve, and replenish the air inside using a vent valve that filters out the intrusion of contaminated air and prevents the intrusion of contaminated liquids from the outside (Figure 11).

[0065] Considering the damage to the cornea caused by frequent use of preservatives and the fact that some people develop hypersensitivity to certain preservatives, such as benzalkonium chloride (the most common preservative), the use of the system described in the present invention can minimize the risk of long-term use of medicines. In this sense, frequent use of preservatives has been shown to weaken the ocular epidermis, making it very vulnerable.

[0066] In related embodiments, the system provides all the elements necessary to administer an artificial tear composition in a safe and convenient manner.

[0067] Another embodiment of this system allows for the administration of an artificial tear composition without the need for antimicrobial and antistatic additives, preserving a sterile solution.

[0068] In another related embodiment, the system is capable of storing and administering the artificial tear compositions of the present invention at an ideal pH of 6.5 to 7.5 and an osmolality of 200 to 400 mosmol / kg.

[0069] And in a related embodiment, the system includes a borate-based buffer solution in a range not exceeding 0.1%.

[0070] In another related embodiment, the system is understood to be sodium hyaluronate in a ratio corresponding to borate buffer where further stability of sodium hyaluronate is observed, for example:

[0071] [Table 3]

[0072] Another aspect of the present invention is that the system and artificial tear composition maintains common parameters of the contact lens, such as overall diameter, thickness, UV transmittance, and diopter.

[0073] (Example) The present invention will now be described with reference to specific examples, which are merely for illustrating the features and advantages of the present invention and are not intended to limit the scope of application or embodiments of the present invention.

[0074] Example 1 [Table 4]

[0075] Example 2 The artificial tear composition of the present invention has the following properties with respect to the microscopic morphology of micelles (oil particles), particle size distribution, conductivity, zeta potential, electrophoretic mobility, compatibility with contact lenses, and emulsion homogeneity.

[0076] a) Microscopic characterization The first objective of the evaluation was to compare the composition of the present invention (referred to herein as "PRO-176") with the commercially available SYSTANE BALANCE (R)The objective of this study was to determine the morphological differences and / or similarities between the nanoemulsions and the crystalline emulsions. This evaluation was based on the paper "Electron microscopy of nanoemulsions: An essential tool for characterization and stability assessment" (Klang et al., 2011), published in Micron, Issue 43, 2012. This paper used a transmission electron microscope (TEM) and sample processing using the cryo-plung technique. This evaluation was conducted in collaboration with the National Polytechnic University (Instituto Politecnico Nacional) in Mexico City.

[0077] These results suggest that PRO-176 (Fig. 1B) and SYSTANE BALANCE (R) In the case of (Figure 1A), the difference in contrast between the surrounding layers of the castor oil particles was observed in the TEM image. (R) In PRO-176, a darker layer is observed due to the low charge density of dimyristyl phosphatidylglycerol (DMPG), whereas in PRO-176, a lighter layer is observed due to the high charge density of dimyristyl phosphatidylcholine (DMPC).

[0078] b) Particle size distribution SYSTANE BALANCE WITH PRO-176 (R) The particle size distribution was characterized using a Malvern Zetasizer Nano ZSP (Red badge).

[0079] Regarding particle size distribution, SYSTANE BALANCE (R)For PRO-176 (Figure 2A), a population mean of 110.3 d.nm was obtained, with a distribution of 28.21 d.nm to 531.2 d.nm. Within this range, a particle size of 141.8 d.nm was the most prevalent. For PRO-176 (Figure 2B), a population mean of 83.11 d.nm was obtained, with a distribution of 32.67 d.nm to 255.0 d.nm. Within this range, a particle size of 91.28 d.nm was the most prevalent. Comparing the evaluation results of these two products, the particle size distribution of PRO-176 was significantly higher than that of SYSTANE BALANCE. (R) It is found to be more uniform compared to

[0080] c) Zeta potential This study was conducted using a Malvern Zetasizer Nano ZSP (Red badge) to evaluate the electrostatic charge or zeta potential characteristics that DMPC provides to formulations of PRO-176, and to assess the SYSTANE BALANCE (R) The aim was to examine the differences and / or similarities with the charge or zeta potential provided by the formulation DMPG.

[0081] Therefore, since the index required to measure the zeta potential using a Malvern Zetasizer Nano ZSP (Red Badge) is the viscosity of the sample, measurements were performed according to the Brookfield Viscometer DVT Extra procedure. Based on this result, the zeta potential measurement method was carried out according to the steps specified in the procedure for the Malvern Zetasizer Nano ZSP (Red Badge). The results are shown in the table below.

[0082] [Table 5]

[0083] The zeta potential result for PRO-176, lot 031740 (Figure 3B) was -32.6 mV, consistent with the SYSTANE BALANCE (R) (Figure 3B) For lot 263865F, it was -10.7 mV.

[0084] Zeta potential indicates the stability of nanoemulsions based on the charge interactions that exist between the lipid particles (liposomes) and the surrounding medium (system). Therefore, when classifying nanoemulsions based on their zeta potential, values ​​closer to 0mV (the isoelectric point) are considered less stable, while values ​​above + / - 30mV are considered more stable.

[0085] Based on these results and the comparisons made above, the composition of PRO-176 (zeta potential = -32.6mv) is comparable to the SYSTANE BALANCE (R) (Zeta potential -10.7 mV) indicates stability.

[0086] d) Electrophoretic mobility The purpose of this test was to measure the electrophoretic mobility value that DMPC imparts to the composition of the present invention. (R) The contribution of DMPG contained in the formulation was also examined. In this measurement, conductivity data for the two formulations was also obtained.

[0087] Electrophoretic mobility refers to the speed at which a positively or negatively charged particle moves to an electrode of opposite charge, and is therefore expressed in units of velocity (µm cm / Vs).

[0088] SYSTANE BALANCE (R) The electrophoretic mobility of PRO-176 (Figure 4A) is -0.3696 μm cm / Vs, and that of PRO-176 (Figure 4B) is -1.029 μm cm / Vs. Both values ​​are close to zero on the negative scale, indicating that both products contain anionic charge control agents. However, SYSTANE BALANCE (R) The conductivity of the product (2.47 mS / cm) is higher than that of PRO-176 (0.379 mS / cm). This represents a reference value for the ionic charge in the formulation. (R)In this case, the price is even higher due to the number and quantity of ingredients in the formulation.

[0089] In another test carried out on electrical conductivity, the same equipment was used to test the commercial product SYSTANE BALANCE (R) The fatty acids used in each formulation were compared with those in the previous study and the components were characterized.

[0090] The conductivity meter used was a SEVEN Go (Mettler Toledo). The method consisted of steps well known to experts in this field, and each formulation (PRO-176 and SYSTANE BALANCE (R) Two lots of each were used. Taking into account the viscosity of the sample at 25°C, the refractive index and dielectric constant of water (1.33 / 78.50) were applied.

[0091] The results are as follows: [Table 6]

[0092] Conductivity is an index that is inversely proportional to the resistivity of a medium to particles in the medium. High conductivity reduces the resistance between charged oil particles, causing bonding between the particles. This results in coalescence and separation of the oil and water phases. Therefore, the lower the conductivity, the more stable the product.

[0093] e) Contact lens compatibility Contact lens use is associated with eye irritation due to their long residence time on the ocular surface, and some contact lens wearers may need to maintain optimal ocular lubrication to avoid the mechanical effects of lens friction on the ocular surface.

[0094] This study examines the composition of PRO-176 and SYSTANE BALANCE (R) The purpose of this study was to evaluate the product when used in combination with soft contact lenses.

[0095] The study evaluated contact lenses from two manufacturers at two diopters each. The study assessed the physical changes associated with the use of the two formulations. The study was conducted in accordance with ISO 11981:2009 and evaluated the following parameters: diameter, thickness, UV transmittance, and diopter.

[0096] The two tables below show the results, one for each contact lens manufacturer. The tables show the damage caused by each product. The damage to contact lenses is determined by the analyzed indicators.

[0097] [Table 7]

[0098] From the table above, SYSTANE BALANCE (R) It is found that the product affects the UV transmittance, overall diameter, and thickness of the contact lens.

[0099] [Table 8]

[0100] The table above shows the SYSTANE BALANCE for a diopter 1.0 IV type lens. (R) Indicates the product's effect on the overall diameter of this contact lens.

[0101] For composition PRO-176, the SYSTANE BALANCE was 0.01 at the two diopters analyzed (1.0 and 6.0). (R) There was no change in either type of contact lens compared to the changes or changes that occur in lenses that have been exposed to the product.

[0102] f) Emulsion homogeneity Commercially available SYSTANE BALANCE (R) The product label states that it should be "shaken well" before use.

[0103] In the case of PRO-176, a "particle size distribution" test showed that the particle size ranged from 32.67 d.nm to 255.0 d.nm, which is smaller than that of commercially available products (28.21 d.nm to 531.2 d.nm), so there is no need to use such a label.

[0104] This difference can be observed macroscopically when the commercial product (Figure 5A) is left in a test tube at 60°C for 21 days (to promote phase separation of the emulsion), forming a waxy layer that adheres to the walls of the test tube.

[0105] Conversely, when this test was performed on the PRO-176 composition (FIG. 5B), fewer layers were observed and the appearance was more homogeneous to the naked eye.

[0106] Meanwhile, tolerance analysis was performed using the control solution (NaCl), the composition of the present invention, and the commercial product to determine the condition of the contact lenses under test. Each attribute analyzed was plotted and compared with established limits. Lens diameter Type I Diopter 1.0 Number of cases: 180 Dependent variable: diameter (mm) Limits: Upper limit 14.7, middle limit 14.5, lower limit 14.3 Wear time: 30 days

[0107] Figure 6 shows a contact lens with an irregular diameter. This shows the difference between the control solution (NaCl 0.9%) and the commercial product SYSTANE BALANCE (R) The contact lenses using PRO-176 remained within the specifications. Lens thickness Type I diopter 1.0 Number of cases: 180 Dependent variable: Thickness (mm) Limits: Upper limit 0.19, middle limit 0.17, lower limit 0.15 Wear time: 30 days

[0108] Figure 7 shows contact lenses with irregular thickness. This is a comparison of the control solution of NaCl 0.9% and the commercial product SYSTANE BALANCE (R) The contact lenses using PRO-176 remained within the specifications. Lens diameter: I type Diopter: 6.0 Number of cases: 180 Dependent variable: diameter (mm) Limits: Upper limit 14.7, middle limit 14.5, lower limit 14.3 Wear time: 30 days

[0109] Figure 8 shows the comparison of the control solution of NaCl 0.9% and the commercial product SYSTANE BALANCE (R) The data for the diameter of contact lenses tested with PRO-176 shows that they are out of specification. The diameter of contact lenses tested with PRO-176 remains within specification. UV Transmittance Lens Type IV Diopter 6.0 Number of cases: 180 Dependent variable: UV light transmittance (%) Limits: Upper limit 35, middle limit 30, lower limit 25 Wear time: 30 days

[0110] Figure 9 shows contact lenses filled with a 0.9% NaCl control solution whose UV transmittance tends to be at the upper and lower limits, and which are out of specification. PRO-176 and the commercially available product are within the specification, but the commercially available product tends to be at the lower limit. Diopter Lens Type IV Diopter 6.0 Number of cases: 180 Dependent variable: diopters Limits: Upper limit 6.25, middle limit 6.00, lower limit 5.75 Wear time: 30 days

[0111] Figure 10 shows out-of-specification values ​​for contact lenses tested with the 0.9% NaCl control solution and the commercial product. No out-of-specification diopters occurred with PRO-176-treated contact lenses during testing.

[0112] Example 3 polydispersity index One of the main characteristics of an O / W emulsion is the oil particle size distribution. This characteristic is closely related to the stability and maintenance of its physicochemical properties. This is because if the oil particle size varies widely, the particles will aggregate and the lipid and aqueous phases will separate. This distribution pattern or morphology is called polydispersity.

[0113] The polydispersity index (Pdi) of the composition of the present invention (PRO-176) was evaluated using a Zetasizer Nano ZSP type instrument, in comparison with the aforementioned commercially available product. The viscosity of the sample was measured using the refractive index and dielectric constant of water (1.33 / 78.50, respectively) at a temperature of 25°C.

[0114] The results are shown below. [Table 9]

[0115] According to the results in the previous table, PRO-176 has a smaller polydispersity index (0.215 Pdi) and average particle size (83.03 d.nm) compared to the commercial product (0.247 Pdi, 110.63 d.nm). This is due to the difference in the amount and type of dispersing oil in the two formulations, as well as the surfactants and dispersants used in each formulation, considering the non-uniform particle size compared to PRO-176 (propylene glycol 0.6%).

[0116] Numerous modifications and alternative embodiments of the present invention will occur to those skilled in the art having the benefit of the foregoing description and the associated drawings. Therefore, it is understood that the invention is not limited to the specific embodiments described, and that modifications and alternative embodiments are intended to be included within the scope of the appended claims. Specific terms used herein are used in a generic and descriptive sense and not for purposes of limitation.

Claims

1. An ophthalmic pharmaceutical composition in the form of an oil-in-water (O / W) nanoemulsion, characterized in that it comprises: a) Organic polyol compound b) Sodium hyaluronate polymer c) at least one synthetic phospholipid of the phosphatidylcholine type, and d) at least one pharmaceutically acceptable excipient e) Castor oil wherein the sodium hyaluronate polymer is high impact emulsified; The organic polyol compound is selected from the group consisting of propylene glycol, polyethylene glycol 300, and sorbitol. The at least one pharmaceutically acceptable excipient is selected from the group consisting of surfactants, boric acid, sodium borate decahydrate, edetate disodium dihydrate, glycerin, and mixtures thereof.

2. 2. The composition according to claim 1, wherein the synthetic phospholipid is selected from the group consisting of DPPC (1,2-dipalmitol-sn-glycero-3-phosphocholine), DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), DEPC (1,2-dierythroyl-sn-glycero-3-phosphatidylcholine), and DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine).

3. 3. The composition according to claim 1 or 2, characterized in that: The organic polyol compound is present in a proportion of 0.1 to 0.6% w / v. Sodium hyaluronate at a ratio of 0.1 to 0.5% w / v. DMPC at a ratio of 0.001 to 0.01% w / v. Castor oil in a proportion of 1.0 to 5.0% w / v.

4. 4. A composition according to any one of claims 1 to 3, characterized in that the particle size distribution in the micelles formed with said synthetic phospholipids is between 30 and 260 nm, preferably between 32 and 255 nm, preferably between 82.5 and 92.5 nm.

5. A method for producing an artificial tear composition for an ophthalmic pharmaceutical composition according to any one of claims 1 to 4, comprising the following steps: Adding water for injection to a stainless steel tank at a temperature of -20°C to 30°C in an amount of 60-65% of the total composition volume. - Adding surfactant, DMPC, boric acid, sodium borate decahydrate, edetate disodium hydrate, glycerin, propylene glycol, sodium hyaluronate, castor oil while constantly stirring. - A mechanical emulsification step is carried out until a completely homogeneous product is obtained. Sterilization of the emulsion by filtration through a sterile membrane with a pore size of 0.2 μm. The mixture is then subjected to a 60 minute homogenization step and three cycles of mechanical emulsification at a pressure of 10,000 psi to 30,000 psi.

6. A pharmaceutical system characterized by: - low density polyethylene container with assembled high density polyethylene locking mechanism with silicone and low density polyethylene valve system, an ophthalmic pharmaceutical composition according to any one of claims 1 to 4, and - Less than 0.1% borate-based buffer.

7. The system described in claim 6, characterized in that the ophthalmic pharmaceutical composition described in claims 1 to 4 is suitable for storage and administration at a pH of 6.5 to 7.5 and an osmotic pressure of 200 to 400 mOsmol / kg.

8. A method comprising packaging the ophthalmic pharmaceutical composition of claim 1 in a system according to claim 6 or 7.

9. 5. The ophthalmic pharmaceutical composition according to claim 1, which has characteristics suitable for maintaining the diameter of a soft contact lens by 1.5% to 2.0%, the thickness of a soft contact lens by 10.0%, the ultraviolet transmittance value of the soft contact lens within a range of ±5.0% of the initial value, and the display diopter of the soft contact lens by ±25%.

10. 8. A pharmaceutical system according to claim 6 or 7 for use in the treatment of dry eye and non-bacterial conjunctivitis.

11. 5. The ophthalmic pharmaceutical composition according to any one of claims 1 to 4, for use in the treatment of dry eye and non-bacterial conjunctivitis.

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