Ophthalmic compositions for treating visual impairment

Abstract

This invention provides an ophthalmic composition for treating and / or preventing visual impairment caused by changes in the structure of the eye's lens, specifically involving alterations in the proteins that form the lens. The ophthalmic composition comprises a combination of a therapeutically effective amount of a polyphenolic compound and a terpene compound, or their salts or crystalline forms, requiring low doses of the bioactive compound to treat the disease with reduced frequency of administration. In particular, the ophthalmic composition of this invention can be used to treat and reverse visual impairments caused by changes in lens structure, such as cataracts, by reversing the lens opacity caused by the disease.

Description

[0001] This invention is a divisional application of the invention patent with application number 202280065540.0, application date August 5, 2022, and invention title "Ophthalmic Composition for Treating Visual Impairment". Technical Field

[0002] This invention relates to healthcare, and more particularly to ophthalmic compositions for treating visual impairments, especially those affecting the normal function of the lens of the eye. Background Technology

[0003] Visual impairments affecting the regular structure of the lens of the eye are those conditions that modify or alter the proteins that make up the lens and cause visual damage. The clarity and / or hardness of the lens frequently change due to the aggregation of lens proteins (lens proteins). This type of recurring condition is called a "cataract." As used in this invention, the term "cataract" refers to a condition where the lens of the eye becomes cloudy due to structural changes and / or aggregation of proteins, thereby reducing the amount of light entering the eye and causing visual impairment. Cataracts can form congenitally, in adolescents, age-related, or secondary to diseases (diabetes, myotonic dystrophy, galactosemia, neurofibromatosis type 2, rubella, etc.), trauma, etc. Cataracts can be nuclear, cortical, or posterior subcapsular. However, other diseases are associated with changes in lens structure, such as presbyopia, lens sclerosis, retinal degeneration, Refsum disease, Smith-Lemli-Opitz syndrome (SLOS), drusen, Schneider crystalline keratopathy (SCD), abeta-lipoproteinemia (ABL), familial hypobeta-lipoproteinemia (FHBL), aging, macular degeneration, and diabetic retinopathy.

[0004] Treatment for these conditions depends on the underlying cause, so all pathologies that can be pre-determined for their development should be addressed first. Symptoms of some of these conditions (such as early-stage cataracts) can be reduced by using prescription lenses, sun-protective lenses, or medications such as drops, ointments, and pills.

[0005] Another alternative form of treatment is surgery. It should be noted that for surgery to be performed, the cataract should be in its mature or opaque stage; before this, corrective measures using lenses are only intended to reduce refractive errors caused by the development of opacity. It is worth mentioning that cataract surgery, which consists of removing the lens and replacing it with an artificial lens, has disadvantages such as high cost and side effects (such as posterior capsule rupture and corneal edema).

[0006] Due to problems caused by surgery, existing technologies have explored the possibility of using bioactive compounds to treat visual impairments.

[0007] The most studied bioactive compound to date is likely a terpenoid, specifically lanosterol, whose use in cataract reversal remains unproven. The most successful experiments with this compound were conducted by Zhao et al. (Zhao et al., Lanosterol Reverses Protein Aggregation in Cataracts. Nature. 2015;523: 607–611). They were able to demonstrate that using 14 intravitreal injections (final dose 1.4 mg) of lanosterol-loaded nanoparticles, along with 50 µL of lanosterol drops three times daily for six weeks, reduced the cataract stage in a group of seven dogs by up to two grades. Unfortunately, the number of injections required to achieve these results was too high, thus not significantly reducing the risk associated with surgery or eliminating problems in advanced cases.

[0008] Following the efforts of Zhao et al., other authors have yet to come close to similar results. Chen et al. (Chen et al., Lanosterol and 25-hydroxycholesterol Dissociate Isolated Crystalline Aggregates from the Human Cataract Lens Through Different Mechanisms. Biochemical and Biophysical Research Communications. 2018; 506(4):868-873) demonstrated positive in vitro activity of lanosterol by adding 10 μM and 200 μM lanosterol, along with 10 μM and 200 μM 25-hydroxycholesterol, to 2 mg / mL protein aggregates obtained from surgically removed cataracts for 14 days. Macroscopic review showed that after 6 days of treatment at room temperature, lanosterol and 25-hydroxycholesterol significantly cleared the initially dark solution in a dose-dependent manner. The authors found that the effectiveness of these compounds was highly dependent on the degree or severity of the cataract. However, this study showed that in the cortical cataract group, the concentration required to achieve 50% of the estimated mean maximum production effect (EC50) increased by 0.5 to 3 times compared to the nuclear cataract group. Furthermore, the amount of protein released decreased with increasing severity. As reported by Zhao et al., this study demonstrated limitations and confirmed the need for high-dose and high-frequency treatment. It is also possible that these compounds may not penetrate the lens of individuals with severe nuclear cataracts. Therefore, in practice, the effective concentration of compounds for use in the lens of individuals with mature or dense cataracts may be several hundred times the EC50 value measured in vitro.

[0009] Daszynski et al. (Failure of Oxysterols such as Lanosterol to Restore the Clarity of the Cataract Lens. Scientific Reports. 2019; 9:8459) conducted in vitro cataract reversal studies on rat lenses and protein solubilization studies on human lenses only. A liposomal solution of 15 mM lanosterol could not reverse the opacity or prevent its progression. Instead, all lenses treated with lanosterol progressed to more advanced mature cataracts with significant nuclear involvement. Nagai et al. (Intravitreal Injection of Lanosterol Nanoparticles Rescues Collapse of Lens Structure at an Early Stage in Shumiya Cataract Rats. International Journal of Molecular Sciences. 2020; 21(3):1048) developed an intravitreal injection formulation containing lanosterol nanoparticles (LAN-NP) using a ball milling method, based on the findings of Zhao et al. They evaluated the therapeutic effect of LAN-NP on lens collapse and opacity using two rat cataract models (SCR-N, rats with mild lens collapse) and (SCR-C, a combination of significant lens collapse and opacity). Unfortunately, LAN-NP did not repair lens structure; they only delayed the onset of opacity. Using LAN-NP with lanosterol supplementation did not improve severe lens collapse.

[0010] Shanmugam et al. also found similar results (Shanmugam et al., Effect of Lanosterol on Human Cataract Nucleus. Indian Journal of Ophthalmology. 2015; 63 (12): 888-90). They investigated the effect of lanosterol on the lens nucleus in people with age-related cataracts. They used 40 age-related cataract nuclei removed by manual small-incision cataract surgery, and randomly immersed 20 nuclei in a 25 mM lanosterol solution, while the remaining nuclei were stored in the dark for 6 days in a control solution without lanosterol. The conclusion was that the 25 mM lanosterol solution did not reverse the opacity of the lens nucleus in age-related cataracts.

[0011] Patent US10471076B2 describes a method for treating or preventing visual impairment using lanosterol. The paper proposes administering a dose of the compound, from 0.1 mg to 5 g, via a systemic route to a person weighing approximately 70 kg; for example, a unit dose of 1 mg to 2.5 g of the compound. However, to evaluate the effect of lanosterol on reducing cataracts in lens tissue, naturally occurring cataract lenses from rabbits were isolated and incubated for 6 days in a solution containing 25 mM lanosterol. Subsequently, lens clarity was compared before and after lanosterol treatment, yielding a solid trend of reduced cataract severity, as confirmed by increased lens clarity. The information presented in this patent is no different from information reported in other references regarding limitations found in the use of lanosterol in the treatment of cataracts, specifically as reported by Shanmugam et al., using the same concentration of lanosterol.

[0012] Patent CN106344587A describes the preparation of lanosterol compounds for ocular use, particularly pharmaceutical compositions containing 5 mM-250 mM lanosterol compounds, methods for preparing such pharmaceutical compositions, and the use of such pharmaceutical compositions in the prevention and treatment of ocular diseases. The composition, in the form of eye drops containing 25 mM lanosterol (11.4 mg / mL), was administered to canines (Canis familiaris L.) three times daily: 50 μL of 25 mM lanosterol in the morning, afternoon, and evening, with an interval of at least 5 hours between each administration, for 12 consecutive weeks. Although no definitive data are presented, it is suggested that the composition can completely cure traumatic cataracts within 2 weeks; however, subsequent experimental evidence does not support its use, particularly in higher-grade advanced cataracts.

[0013] The paper also proposes chemical modifications of lanosterol to enhance its effects. Patent application WO2019097434A1 relates to compositions of lanosterol and 25-hydroxycholesterol derivatives (including their pharmaceutically acceptable salts) for use in combination with oxidative protectants, free radical scavengers, regulators of protein carbonylation, lipid peroxidation, oxidoreductase enhancers, or antioxidants. The paper proposes inhibitory concentrations of lanosterol derivatives ranging from 0.010 wt% to approximately 5 wt% %. Imaging was performed on patients diagnosed with cataracts and exhibiting lens opacity prior to treatment. Although the paper reports “significant improvement in lens opacity after 3 weeks and almost complete elimination of opacity after 6 weeks,” no measurements of grade reduction in cataract development stage are reported. Therefore, it is unclear whether the modifications performed can be used in cases of advanced cataracts.

[0014] Patent application US2020016176A1 describes an aqueous ophthalmic composition for treating eye diseases, injuries, or damage, comprising steroids such as lanosterol in combination with other steroids. However, it highlights the importance of excipients in the final therapeutic effect, using 2-hydroxypropyl-β-cyclodextrin (CD) and hydroxypropyl methylcellulose (HPMC). They conducted a precise study on the treatment of cataract lenses in three different breeds of dogs using an injection regimen of nanoparticles loaded with a steroid formulation (100 μg). These included lanosterol and another cholesterol-derived steroid, in volumes equivalent to 50 μL (1 drop), administered three times daily at approximately 7 AM, 1 PM, and 4 PM for three weeks. Experimental data showed a maximum improvement of 20% in the dogs used in this study.

[0015] Other bioactive compounds that have been tried for the treatment of cataracts are naturally derived polyphenolic compounds, particularly curcumin.

[0016] Curcumin has been reported to inhibit sodium selenite-induced oxidative stress, as in the case of Manikandan et al. (Manikandan et al., Effect of Curcumin on Selenite-Induced Cataractgenesis in Wistar Rat Pups. Current Eye Research. 2010; 35:122-129). They investigated the antioxidant potential of curcumin in sodium selenite-induced (15 µM / kg body weight) cataracts in rat pups. This group of researchers concluded that treatment with curcumin (75 mg / kg body weight as a single dose) resulted in significant reductions in lipid peroxidation levels, enzyme antioxidant levels, and non-enzymatic antioxidant levels, supporting the possibility that free curcumin in food may help prevent the onset of age-related cataracts. In another work, Manikandan et al. (Effect of Curcumin on the Modulation of αA- and αB-crystallin and Heat Shock Protein 70 in Selenium-Induced Cataractgenesis in Wistar Rat Pups. Molecular Vision. 2011; 17:388–394.) investigated the expression of αAa and αB-crystallin and heat shock protein 70 (Hsp 70) during curcumin treatment for sodium selenite-induced cataract formation in Wistar rat pups. They similarly concluded that curcumin inhibited the expression of αAa and αB-crystallin induced by selenite and Hsp 70. Therefore, curcumin can inhibit and / or prevent cataract formation in rat pups.

[0017] Regarding the efficacy of curcumin in prevention and treatment, Yogaraj et al. (Yogaraj et al., Quaternary Ammonium Dendrimeric Poly (Amidoamine) Encapsulated Nanocurcumin Effectively Prevents Cataracts in Rat Pups by Regulating Pro-Inflammatory Gene Expression. Journal of Drug Delivery Science and Technology. 2020; 58:1773-2247) developed and characterized a nanocurcumin formulation using a functionalized polyamidoamine dendrimer (PAMAM) (third generation) encapsulated with curcumin. They tested their formulation in Wistar rat pups in the same model as the Manikandan group, using an in vitro human lens epithelial cell (HLE-B3) system to express pro-inflammatory genes. Their results showed that nanocurcumin was as effective as free curcumin in reducing sodium selenite-induced cell death, RNA degradation, and iNOS (inducible nitric oxide synthase) gene expression levels. Therefore, they concluded that the curcumin formulation encapsulated with QPAMAM compensated for the main limitations of the free counterpart by preventing oxidative-mediated cataract development, with higher solubility, sustained release and higher bioavailability.

[0018] CN106511269A also describes an ophthalmic nanosuspension formulation and its preparation method. Specifically, this ophthalmic nanosuspension formulation is prepared by combining an ophthalmic pharmaceutical adjuvant with curcumin. Ophthalmologically acceptable gel and nanosuspension formulations of curcumin were tested in the same rat model with selenite-induced cataracts. Administration at a 3-times / 8-day regimen demonstrated beneficial effects of the curcumin ophthalmic nanosuspension. Evidence suggests better bioavailability and a larger surface area to improve drug absorption, thereby prolonging the duration of action. However, reversal was not demonstrated in vivo, but enzyme activity was characterized in vitro.

[0019] Patent EP2346520B1 relates to an aqueous ophthalmic composition comprising natural curcuminoids, such as curcumin, bisdemethoxycurcumin, demethoxycurcumin, and synthetically derived curcumin and / or other demethoxycurcuminoids, which, alone or in combination with a suitable surfactant and co-solvent as a penetration enhancer, along with other ophthalmic excipients, can be used to treat eye diseases or disorders. Similar to other curcumin-related papers, the conclusion is that instilling a 98% curcumin ophthalmic formulation into the eyes of Wistar rat pups effectively reduced selenite-induced cataracts, demonstrating a preventative effect.

[0020] However, experimental evidence for naturally derived polyphenolic compounds, such as curcumin, shows that they can only prevent the formation of highly advanced cataracts, not reverse them. Similarly, the development of compositions based on terpenoid compounds such as lanosterol has achieved minimal reductions in cataracts through repeated and very aggressive treatment at high doses. Efforts to develop compositions based on these types of bioactive compounds have not yet resulted in significant reductions or elimination of cataracts.

[0021] For the reasons mentioned above, we have sought to address the problems of currently used ophthalmic compositions for treating visual impairments by developing a composition that, in addition to allowing for the reversal of progression to advanced cataracts, also requires low dosage and fewer effective application times.

[0022] Invention Theme

[0023] In view of the deficiencies of the prior art, one of the subjects of the present invention is to provide an ophthalmic composition for treating visual impairments that requires low doses of bioactive compounds to reverse and / or prevent changes in the regular structure of the lens of the eye, primarily those conditions that modify or alter the proteins that form it.

[0024] Another subject of the present invention is to provide an ophthalmic composition for treating visual impairments, which requires fewer applications to effectively treat this type of impairment.

[0025] These and other topics are achieved through ophthalmic compositions for treating visual impairments according to the present invention. Summary of the Invention

[0026] To achieve the objectives of this invention, an ophthalmic composition for treating visual impairment has been invented. This ophthalmic composition is characterized by comprising a combination of therapeutically effective amounts of polyphenolic compounds and terpenoid compounds, allowing for the restoration and / or prevention of alterations to the regular structure of the lens, primarily those conditions involving modifications or alterations to the proteins that form the lens.

[0027] Other aspects of the invention include methods for manufacturing the ophthalmic compositions of the invention, and their use in treating ophthalmic diseases caused by protein alteration or aggregation. Attached Figure Description

[0028] The novel aspects considered to be features of the invention will be set forth in detail in the appended claims. However, some embodiments, features, and some objects and advantages thereof will be better understood in the detailed description when read in conjunction with the accompanying drawings, wherein:

[0029] Figure 1 These are a set of photographs of different stages of lens opacity in laboratory animals, to show the different degrees of cataract development.

[0030] Figure 2 This is a set of photographs of the lenses of healthy controls and diseased control animals with grade 4 cataracts.

[0031] Figure 3 This is a set of photographs of animal lenses before and after treatment with curcumin nanoemulsion applied intraocularly.

[0032] Figure 4 This is a set of photographs of the lens of animals before and after treatment with lanosterol nanoemulsion.

[0033] Figure 5 This is a set of photographs of animal lenses before and after treatment with a curcumin nanoemulsion containing lanosterol in a 1:1 ratio.

[0034] Figure 6 This is a set of photographs of animal lenses before and after treatment with a curcumin nanoemulsion containing lanosterol in a 1:3 ratio.

[0035] Figure 7 This is a set of photographs of animal lenses before and after intraocular treatment with free curcumin.

[0036] Figure 8 This is a set of photographs of the animal lens before and after intraocular treatment with free lanosterol. Detailed Implementation

[0037] It has been found that alterations to the regular structure of the lens, primarily those conditions that modify or alter the proteins that form the lens, can be reversed and / or prevented with fewer applications in several known visual disorders, and that ophthalmic compositions containing therapeutically effective amounts of polyphenolic compounds in combination with terpenoids or their corresponding pharmaceutically acceptable salts or crystalline forms may be effective in treating those visual disorders.

[0038] The novel combination of polyphenolic compounds and terpenoids exhibits a synergistic effect, allowing for the reversal and / or prevention of changes in lens structure at lower doses with fewer application times and shorter durations, and is more effective than those reported in the prior art for individual compounds.

[0039] According to the principles of the present invention, the ophthalmic composition may contain any ratio of polyphenolic compounds and terpenoids. In a preferred embodiment, the ophthalmic composition of the present invention contains a polyphenolic compound in a ratio of 1:10 to 10:1 to a terpenoid, preferably in a ratio of 1:3 to 3:1 to a terpenoid, and more preferably in a 1:1 ratio.

[0040] In a preferred embodiment of the invention, the polyphenolic compound is a natural curcuminoid, preferably selected from curcumin; bisdemethoxycurcumin; demethoxycurcumin and bis-O-demethyl synthetic curcumin, and / or other demethoxycurcuminoids; stable isomers of the above substances; or pharmaceutically acceptable salts or crystalline forms thereof, with naturally derived curcumin being particularly preferred due to its antioxidant and anti-inflammatory activity. These compounds have been sufficiently described in the prior art, enabling those skilled in the art to obtain them using the techniques previously described in the background of this invention.

[0041] Terpenoids were selected from lanosterol and its steroid derivatives, dihydrolanosterol; 4,4-dimethylcholest-8 (9); 14,24-trien-3β-ol; 4,4-dimethylcholest-8,24-dien-3β-ol; 4,4-dimethylcholest-8-en-3β-ol; 4,4-dimethylcholest-8 (9); 14-dien-3β-ol; 14-demethyllanosterol; lanosterol; Δ7,24-cholestipenol; cholesterol; cholesterol-7-enol; cholesterol ester; 7-dehydrocholesterol; sterol; 7-dehydrosterol; yeast sterol; 27-hydroxycholesterol; Cholesterol-7,24-dien-3-β-ol; cholesterol-8(9)-en-3-β-ol; 5α-cholesterol-3β-6-one; 5-cholesterol-3β,25-diol; 5-cholesterol-3β,25-OSO3H (5-cholesterol-3β,25-sulfate); 5-cholesterol-3β-OSO3H,25-ol (5-cholesterol-3β-sulfate,25-ol); 5-cholesterol-3β,25-diol; their disulfides and / or esters; stable isomers of the above substances; or pharmaceutically acceptable salts or crystalline forms thereof, with lanosterol and / or derivatives thereof being particularly preferred. Similarly, these compounds have been described in the prior art, making their acquisition readily apparent to those skilled in the art upon reference to the known techniques in the background of this invention.

[0042] In a particularly preferred embodiment, the composition comprises curcumin as a polyphenol compound, preferably obtained from the rhizome of the perennial herb turmeric using techniques described in the prior art.

[0043] In another particularly preferred embodiment, the composition comprises lanosterol as an amphiphilic tetracyclic terpene compound, which is also synthesized from squalene or waxes such as lanolin using techniques described in the prior art.

[0044] Other ophthalmologically acceptable components for preparing the ophthalmic compositions of the present invention are preferably suitably selected for administration via topical, subconjunctival, retrobulbar, periocular, subretinal, suprachoroidal, intraocular, intravitreal, or intraocular routes, including but not limited to pharmaceutical forms selected from: ophthalmic solutions, ophthalmic ointments, ophthalmic irrigation solutions, intraocular infusion solutions, anterior chamber irrigation solutions, medical drugs, injections, as part of ophthalmic implants, or as preservatives for corneal extraction. Ophthalmologically acceptable components and excipients may also be used to formulate the compositions of the present invention, including but not limited to water, buffer solutions or sodium chloride solutions, surfactants or cyclodextrins, emulsions, liposomes, ophthalmologically acceptable gels or suspensions, or combinations thereof. Particularly preferred excipients consist of ophthalmic nanoemulsions.

[0045] The compositions of the present invention can preferably effectively reverse and / or prevent changes in lens structure, primarily changes in lens proteins, by at least a single application of the composition. Therefore, they can be used to treat visual impairments, including cataracts (regardless of their cause), or other diseases associated with changes in lens structure, such as presbyopia, lens sclerosis, retinal degeneration, Refsum disease, Smith-Lemli-Opitz syndrome (SLOS), drusen, Schneider crystalline keratodystrophy (SCD), abetalipoproteinemia (ABL), familial hypobetalipoproteinemia (FHBL), aging, macular degeneration, and diabetic retinopathy. When the disease is cataracts, the compositions of the present invention can almost completely reverse the disease.

[0046] Although techniques for preparing the compositions of the present invention are known in the art, it can be illustratively stated that any known method described in the art, such as that reported by Agame-Lagunes et al. (Agame-Lagunes et al., Curcumin Nanoemulsions Stabilized with Modified Phosphatidylcholine on Skin Carcinogenesis Protocol. Current Drug Metabolism. 2020, 21, (3):226-234), can be used for the inclusion of polyphenolic and terpenoid compounds in ophthalmic nanoemulsions. This typically consists of an oil phase and an aqueous phase containing the compounds, in order to obtain nanoemulsions by methods known in the art (high-energy or low-energy methods, preferably high-energy methods). These methods enable the acquisition of nanoscale particles ranging from 5 nm to 999 nm, preferably between 20 nm and 300 nm, from the preferred oil phase.

[0047] In one specific embodiment, for the formation of nanoemulsions, a combination of aqueous phase to oil phase ratios between 80:20 and 95:5 is provided, with a particularly preferred combination having an aqueous phase content of at least 95%.

[0048] To prepare the nanoemulsions of the compounds of the present invention, the oil phase preferably contains an ophthalmologically acceptable oil, a surfactant, and an organic solvent. The oil is preferred, more preferably a triacylglycerol oil, even more preferably containing a glycerol derivative and three fatty acids, preferably a combination of medium-chain triacylglycerols. The surfactant is also preferably an amphiphilic surfactant of synthetic or natural origin, preferably a natural amphiphilic surfactant, such as phosphatidylcholine, mono- and diacylglycerols, more preferably phosphatidylcholine. The ophthalmologically acceptable organic solvent is preferably an alcohol, most preferably with 1 to 3 carbon atoms, particularly preferably ethanol.

[0049] Regarding the aqueous phase, a preferred embodiment comprises deionized water and glycerol as a stabilizer to form an ophthalmologically acceptable excipient. In a preferred embodiment of the invention, the aqueous phase comprises 5% to 60% glycerol, preferably in the range of 10% to 45%, and even more preferably in the amount of 15% to 25% glycerol.

[0050] An ophthalmic composition is prepared according to the principles of the invention for the treatment and / or prevention of visual impairment caused by changes in the structure of the ocular lens, particularly visual impairment related to protein alterations. This ophthalmic composition is in any pharmaceutical form suitable for application to the eye. It is intended to almost completely reverse said visual impairment, and is preferably used in at least one administration to achieve reversal within up to 7 days after treatment.

[0051] The invention will be better understood through the following examples. They are for illustrative purposes only, to allow for a thorough understanding of the preferred embodiments of the invention and to guide their implementation. This does not imply that there are no other embodiments (not shown) that can be implemented based on the foregoing description.

[0052] Example

[0053] A. Preparation of ophthalmic compositions for use in the prior art and the present invention.

[0054] To demonstrate the novel effects of the compositions of the present invention, six examples of the compositions shown in Table 1 were prepared on a 10 mL basis using curcumin as a polyphenol and lanosterol as a terpene compound, as they are the most studied in the prior art:

[0055]

[0056] Table 1 - Evaluation of ophthalmic compositions

[0057] To prepare the nanoemulsion to be tested, an oil phase (to be dispersed) was obtained by combining curcumin and / or lanosterol according to the table with 10% phosphatidylcholine, 3 mL ethanol, and 5% medium-chain triacylglycerol. Once the combination of compounds for use in this invention was prepared, the oil phase was subjected to a double-bain-marie treatment to remove excess organic solvents prior to homogenization.

[0058] The aqueous phase (dispersant) consisted of 60% water and 25% glycerol. The two phases were manually encapsulated in an ULTRA-TURRAX digital T25 rotor-stator homogenizer (IKA Works, Inc. Staufen, Germany) for further processing, producing a crude emulsion. This crude emulsion was then sonicated using a Branson Digital Sonifier S-450D (Branson Ultrasonic Corp., Danbury, CT) to reduce particle size, thus obtaining the associated nanoemulsion.

[0059] The composition was sterilized using a UV lamp. For sterilization, the system was poured into a 10 mL sterile culture plate and then kept uncovered under UV light for 40 minutes. The system was then collected using a sterile syringe into glass vials sealed with paraffin film until used in animal models. All procedures were performed under aseptic conditions.

[0060] Furthermore, compositions E5 and E6, each containing free curcumin (C) and free lanosterol (L), were prepared by dissolving only the compound in the dispersed phase used. In this case, medium-chain triacylglycerols were combined according to the ratios in the table, with a base of 10 mL.

[0061] Cataract induction in B. Wistar rats.

[0062] To evaluate cataract reversal in vivo, 7-week-old albino Wistar rats weighing 120–140 g were randomly assigned to groups (n=3) and kept in a controlled environment with a temperature of 23 ± 2 °C and relative humidity between 40% and 70% in a 12-hour light-dark cycle, with free access to commercial diet and water. Animals were cared for according to Mexican official standard NOM-062-ZOO-1999.

[0063] Sodium selenite was administered intravitreally to induced cataracts in thirty rats. Following treatment, the animals developed the disease, but only 26.66% developed cataracts in both eyes. The remainder developed the disease in only one eye, with a higher incidence in the left eye.

[0064] For intravitreal therapy, in addition to local anesthetics (tetracaine), ophthalmic lubricants (hydroxypropyl methylcellulose), and antibiotics (ciprofloxacin), rats were anesthetized by intraperitoneal injection of Zoltil 50 (40 mg / kg body weight) to avoid infection.

[0065] To perform intravitreal injections, the stereoscope is manipulated during the procedure for greater precision. A 1 mL insulin syringe with a 27S needle is inserted into the vitreous at a 45° angle through the sclera to create a puncture site, allowing for the release of intraocular pressure and the removal of some vitreous fluid. A Hamilton syringe with a 26S removable needle is then inserted into the same puncture site along with a selenite solution, which is injected into the eye chamber, avoiding contact with the lens. The needle is then carefully removed, and a drop of antibiotic is placed in each eye.

[0066] Vitreous opacity following sodium selenite administration was evaluated weekly by slit-lamp microscopy for four weeks, and lens opacity was graded as shown in Table 2 below.

[0067]

[0068] Table 2 - Lens Opacity Levels

[0069] The degree of cataract development is indicated by Figure 1 The image shown in the middle can prove that the lens of an experimental animal is cloudy. Figure 1The zero-order lens (G0), primary lens (G1), secondary lens (G2), tertiary lens (G3), and finally quaternary lens (G4) are shown.

[0070] C. The ophthalmic composition was applied to rats with cataracts.

[0071] Eight groups were formed, with three albino Wistar rats in each group. The healthy negative control group (E0) was not induced with sodium selenite and did not develop cataracts; however, another positive control group or disease control group (E7) was induced with cataracts as described above but did not receive treatment with curcumin or lanosterol or combinations thereof as described in this invention. The remaining groups were treated intravitreally with compositions E1 through E6, using the same technique as for administering sodium selenite, in 5 µL volumes of each ophthalmic composition, administered twice (except for the control group), one week apart, to obtain the results for each rat (R1 through R3) in Table 3.

[0072]

[0073] Table 3 - Results of treatment with ophthalmic composition and control groups E0 to E7

[0074] The extent of cataract development and its reduction can be demonstrated in the graph shown in Table 3, whereby the synergistic effect obtained by the compositions of the present invention (E3 and E4) can be observed, which manages to reverse almost all of the opacity. This even occurs in composition E4, where significantly lower amounts of curcumin and lanosterol achieve more than twice the reversal, and even considering the results based on the prior art and those obtained in Examples E5 and E6, those skilled in the art would not be encouraged to use more lanosterol than curcumin, which shows that reversal is better with curcumin than with free lanosterol.

[0075] When the final turbidity after analysis was confirmed, all the above conditions were observed, with a final turbidity of almost 1 in the composition groups of the present invention. This was highly statistically significant, as tested by the Duncan statistical analysis shown in Table 4, where groups E4 and E3, in subset 2, showed similar results. Table 4 shows the mean final turbidity of the groups in the homoprotic subsets, using a harmonic mean sample size of 3,000.

[0076] In this regard, according to Duncan’s statistical analysis, the optimal treatment corresponds to E3, which is the group present in subset 1 along with E0, indicating that the E3 composition can significantly reverse cataracts by reporting no statistically significant difference from E0 (healthy control).

[0077]

[0078] Table 4 - Duncan statistical analysis of the mean final turbidity in groups E0 to E7

[0079] It is also noteworthy that the difference between the minimum and maximum values ​​of the final turbidity mean in group 3 was one degree (1.3333 to 2.3333), while the difference between the minimum and maximum values ​​of the final turbidity mean in group 2 was 0.3333 (1.0000 to 1.3333). This demonstrates that the treatment using the composition of the present invention is highly effective in the treatment of visual impairment.

[0080] Therefore, novel effects superior to those obtained by the compounds alone have been demonstrated according to the principles of the invention. Furthermore, it will be apparent to those skilled in the art that combinations of other polyphenolic compounds with other terpenoid compounds (which have already demonstrated significantly lower cataract reversal effects on their own in the prior art, equivalent to Examples E1, E2, E5, or E6) can be prepared to obtain synergistic effects equivalent to those obtained with the compositions E3 and E4 shown in the above examples.

[0081] As will be apparent to those skilled in the art from the prior art, the compositions of the present invention can be formulated into different pharmaceutical forms for ophthalmic use. This is because the prior art itself has demonstrated the effects of individual compounds in several ophthalmic compositions, such as topical, subconjunctival, retroocular, periocular, subretinal, suprachoroidal, intraocular, intravitreal, or intraocular applications.

[0082] Based on the foregoing, it will be demonstrated that the ophthalmic composition of the present invention for treating visual impairment has been prepared to reverse and / or prevent such impairment caused by changes in the lens structure (primarily through alterations in lens proteins). It will also be apparent to those skilled in the art that, as described above and illustrated in the figures, embodiments of such compositions are illustrative rather than limiting of the invention, as many considerations regarding its details are possible while still taking into account the scope of the invention.

[0083] Therefore, this invention should not be considered limiting except as required by the prior art and the scope of the appended claims.

Claims

1. An ophthalmic composition, characterized in that, The ophthalmic composition comprises a therapeutically effective amount of a polyphenolic compound and a terpene compound, or their respective pharmaceutically acceptable salts or crystalline forms, wherein the polyphenolic compound is selected from natural curcuminoids or derivatives thereof, and the terpene compound is selected from lanosterol and its steroid derivatives, and wherein the ratio of the polyphenolic compound to the terpene compound is 1:3 to 3:

1.

2. The ophthalmic composition according to claim 1, characterized in that, The polyphenolic compound is selected from curcumin, bis-demethoxycurcumin, demethoxycurcumin, and synthetically derived bis-O-demethylcurcumin, and / or other demethoxylated curcumin compounds, or stable isomers of the above substances.

3. The ophthalmic composition according to claim 2, characterized in that, The polyphenolic compound is natural curcumin.

4. The ophthalmic composition according to claim 1, characterized in that, The terpenoid compounds are selected from lanosterol; dihydrolanosterol; 4,4-dimethylcholest-8(9); 14,24-trien-3β-ol; 4,4-dimethylcholest-8,24-dien-3β-ol; 4,4-dimethylcholest-8-en-3β-ol; 4,4-dimethylcholest-8(9); 14-dien-3β-ol; 14-demethyllanosterol; lanosterol; Δ7,24-cholestipenol; cholesterol; cholesterol-7-enol; cholesterol ester; 7-dehydrocholestyramine; sterol; 7-dehydrosterol; yeast Sterols; 27-hydroxycholesterol; cholesterol-7,24-dien-3-β-ol; cholesterol-8(9)-en-3-β-ol; 5α-cholestan-3β-6-one; 5-cholesten-3β,25-diol; 5-cholesten-3β,25-OSO3H (5-cholesten-3β,25-sulfate); 5-cholesten-3β-OSO3H,25-ol (5-cholesten-3β-sulfate,25-ol); 5-cholesten-3β,25-diol; its disulfate and / or ester; or stable isomers of the above substances.

5. The ophthalmic composition according to claim 4, further characterized in that, The terpene compound is lanosterol.

6. The ophthalmic composition according to claim 3, further characterized in that, The curcumin is derived from the rhizome of the perennial herb turmeric.

7. The ophthalmic composition according to claim 5, further characterized in that, The terpenoid compound is lanosterol, a tetracyclic terpenoid compound that is amphiphilic, synthesized from squalene or waxes such as lanolin.

8. The ophthalmic composition according to claim 1, characterized in that, The ophthalmic composition comprises ophthalmologically acceptable excipients for topical, subconjunctival, retroocular, periocular, subretinal, suprachoroidal, anterior chamber, vitreous, or intraocular application.

9. The ophthalmic composition according to claim 8, further characterized in that, The pharmaceutical form of the ophthalmic composition is selected from ophthalmic solutions, ophthalmic ointments, ophthalmic irrigation solutions, intraocular infusion solutions, anterior chamber irrigation solutions, internal medicine drugs, injections, as part of an ophthalmic implant, or as a preservative for corneal extraction.

10. The ophthalmic composition according to claim 8, further characterized in that, The excipients are selected from water, buffer solutions or sodium chloride solutions, surfactants or cyclodextrins, emulsions, liposomes, ophthalmologically acceptable gels or suspensions, or combinations thereof.

11. The ophthalmic composition according to claim 8, further characterized in that, The ophthalmologically acceptable excipient is an ophthalmic nanoemulsion.

12. The ophthalmic composition according to claim 11, further characterized in that, The ophthalmic composition comprises an oil phase nanoemulsified in an aqueous phase with an average particle size between 5 nm and 999 nm.

13. The ophthalmic composition according to claim 12, further characterized in that, The ophthalmic composition comprises an oil phase with an average particle size between 20 nm and 300 nm.

14. The ophthalmic composition according to claim 12, further characterized in that, The oil phase comprises oil, surfactants, and ophthalmologically acceptable organic solvents.

15. The ophthalmic composition according to claim 14, further characterized in that, The oil in the oil phase is a triacylglycerol ester oil.

16. The ophthalmic composition according to claim 15, further characterized in that, The oil in the oil phase consists of glycerol derivatives and three fatty acids.

17. The ophthalmic composition according to claim 15, further characterized in that, The oil in the oil phase is a mixture of medium-chain triacylglycerol esters.

18. The ophthalmic composition according to claim 14, further characterized in that, The surfactant is an amphiphilic surfactant of synthetic or natural origin.

19. The ophthalmic composition according to claim 18, further characterized in that, The surfactant is selected from phosphatidylcholine, as well as monoacylglycerol esters and diacylglycerol esters.

20. The ophthalmic composition according to claim 14, further characterized in that, The ophthalmologically acceptable organic solvent is alcohol.

21. The ophthalmic composition according to claim 20, further characterized in that, The alcohol has 1 to 3 carbon atoms.

22. The ophthalmic composition according to claim 21, characterized in that, The alcohol in question is ethanol.

23. The ophthalmic composition according to claim 12, further characterized in that, The aqueous phase contains deionized water and glycerol as stabilizers.

24. The ophthalmic composition according to any one of claims 1 to 23, wherein the ophthalmic composition is used to treat and / or prevent ophthalmic diseases caused by alterations in the regular structure of the lens, primarily those diseases that modify or alter the proteins that form the lens.

25. The ophthalmic composition according to claim 24, further characterized in that, The ophthalmic diseases mentioned are selected from cataracts, presbyopia, lens sclerosis, retinal degeneration, Rifsum disease, Smith-Limeley-Oppitz syndrome (SLOS), drusen, Schneider crystalline keratopathy (SCD), abeta-lipoproteinemia (ABL), familial hypobeta-lipoproteinemia (FHBL), aging, macular degeneration, and diabetic retinopathy.

26. The use of a combination of a polyphenolic compound and a terpene compound or their salts or pharmaceutically acceptable crystalline forms in the manufacture of a medicament for the treatment and / or prevention of ophthalmic diseases caused by alterations in the regular structure of the lens, including those diseases involving modification or alteration of proteins that form the lens, wherein the polyphenolic compound is selected from curcuminoids or their derivatives, and the terpene compound is selected from lanosterol and its steroid derivatives, and wherein the ratio of the polyphenolic compound to the terpene compound is 1:3 to 3:

1.

27. The use according to claim 26, wherein the polyphenolic compound is selected from curcumin, bisdemethoxycurcumin, demethoxycurcumin, and synthetically derived bis-O-demethylcurcumin, and / or other demethoxylated curcumin compounds, or stable isomers of the above substances.

28. The use according to claim 26, wherein the polyphenolic compound is natural curcumin.

29. The use according to claim 26, wherein the terpene compound is selected from lanosterol; dihydrolanosterol; 4,4-dimethylcholest-8(9); 14,24-trien-3β-ol; 4,4-dimethylcholest-8,24-dien-3β-ol; 4,4-dimethylcholest-8-en-3β-ol; 4,4-dimethylcholest-8(9); 14-dien-3β-ol; 14-demethyllanosterol; lanosterol; Δ7,24-cholestipenol; cholesterol; cholesterol-7-enol; cholesterol ester; 7-dehydrocholestyramine; sterol; 7-Dehydrosterol; yeast sterol; 27-hydroxycholesterol; cholesterol-7,24-dien-3-β-ol; cholesterol-8(9)-en-3-β-ol; 5α-cholestan-3β-6-one; 5-cholesten-3β,25-diol; 5-cholesten-3β,25-OSO3H (5-cholesten-3β,25-sulfate); 5-cholesten-3β-OSO3H,25-ol (5-cholesten-3β-sulfate,25-ol); 5-cholesten-3β,25-diol; its disulfate and / or ester; or stable isomers of the above substances.

30. The use according to claim 29, wherein the terpene compound is lanosterol.

31. The use according to claim 28, wherein the curcumin is derived from the rhizome of the perennial herb turmeric.

32. The use according to claim 30, wherein the terpene compound is lanosterol, an amphiphilic tetracyclic terpene compound, synthesized from squalene or waxes such as lanolin.

33. The use according to claim 26, wherein the ophthalmic disease is selected from cataracts, presbyopia, lens sclerosis, retinal degeneration, Rifsum disease, Smith-Limeley-Oppitz syndrome (SLOS), drusen, Schneider crystalline keratopathy (SCD), abeta-lipoproteinemia (ABL), familial hypobeta-lipoproteinemia (FHBL), aging, macular degeneration, and diabetic retinopathy.

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