Topical delivery of cannabinoid-based formulations for ocular allergy and inflammation in ophthalmic diseases

Abstract

The present invention relates to the medical device and pharmaceutical industry, as well as related fields such as dermatology and cosmetics, since the formulation includes natural anti-inflammatory components and high viscous solvents such as polysorbate and glycerol, which work synergistically to enhance drug retention on the eye surface, minimize visual blur on instillation and reduce dosage frequency. The present invention describes a topical delivery of a cannabinoid-based ophthalmic composition that includes Tetrahydrocannabinol (THC)-based molecule isolated or associated with Cannabidiol (CBD). In another embodiment of the preferred invention, the formulation further comprises one or more synergistic agents, including but not limited to steroidal and non-steroidal anti-inflammatory and antihistamines pharmaceutical formulations.

Description

[0001] DESCRIPTION

[0002] TOPICAL DELIVERY OF CAN NABINOID-BASED FORMU LATIONS FOR OCU LAR ALLERGY

[0003] AND IN FLAMMATION IN OPHTHALMIC DISEASES

[0004] FIELD OF INNOVATION

[0005] The invention relates to the medical device and pharmaceutical industry, as well as related fields such as dermatology and cosmetics, since the formulation includes natural anti-inflammatory components and high viscous solvents such as polysorbate and glycerol, which work synergistically to enhance drug retention on the eye surface, minimize visual blur on instillation and reduce dosage frequency.

[0006] The present invention describes a topical delivery of a cannabinoid-based ophthalmic composition that includes Tetrahydrocannabinol (THC)-based molecule isolated or associated with Cannabidiol (CBD). In another embodiment of the preferred invention, the formulation further comprises one or more synergistic agents, including but not limited to steroidal and nonsteroidal anti-inflammatory and antihistamines pharmaceutical formulations.

[0007] This ophthalmic solution offers a promising approach to reduce pathogen and allergen-induced cornea and ocular surface inflammation and provide protection enhancement in ophthalmic disease, included but not limited to dry eye disease and neurotrophic keratitis. Another example of the use of this ophthalmic topical application is the management or prevention of dry or wrinkled periocular skin, including the eyelids, with a beneficial outcome for the patient, marking a significant advancement in eyelid inflammation (such as Blepharitis) treatments.

[0008] Treating ocular conditions is challenging for ophthalmologists due to the complexity of ocular anatomy and physiology. Currently available treatments provide relief of symptoms though a long-term treatment using for example buffered solutions of sodium chloride in purified water as eyedrops, also known as artificial tears. However, it is important to note that these methods often fail to address the root causes of the disease, which result in the progression and intensification of the symptoms.

[0009] Topical instillation is a non-invasive technique that involves applying formulations directly to the target area. This reduces the concentration of molecules that are absorbed into the body and maximises the desired bioactive response, usually achieved by the deposition of one or more drops directly onto the ocular surface, leading to the diffusion of these molecules through the corneal and conjunctival barriers and membranes. This innovative solution addresses the limitations and challenges currently faced in the treatment of ocular surface inflammation, offering a significant improvement over other existing methods.

[0010] The formulation THC-based improve and restore the function of the corneal epithelial barrier and help reestablish the tear film balance with the improvement and restoration of the intraocular pressure. In another embodiment of the present invention comprises the THC-based molecules combined with CBD-based molecules, which bring additional anti-inflammatory and antioxidant properties to the proposed formulation.

[0011] In another embodiment of the present invention, the formulation further comprises one or more synergistic applicable agents, either natural or synthetic, including but not limited to steroidal and non-steroidal anti-inflammatory and antihistamines pharmaceutical formulations that provide a synergistic effect and address the underlying inflammatory and oxidative biomolecular mechanisms in unhealthy conditions.

[0012] As cannabinoid-based topical instillation, it will have affinity to the receptors of the endocannabinoid system (ECS) present in the biomolecular membranes and structures of the human eye. This leads to a targeted delivery of the intended formulations. Therefore, this invention is in the technical domain of medical device and pharmaceutical industry, and related ones.

[0013] In parallel, the cannabinoid-based composition are formulated as a topical product for the treatment and prevention of symptoms of dry periocular skin and eyelids along with corneal protection, as the latest innovation in the dermocosmetic field, including but not limited for periocular dermatitis and skin care moisturiser.

[0014] BACKGROUND

[0015] At the forefront of the present invention lies the acknowledgment of the ocular surface as a dynamic interface between the external environment and the delicate structures of the eye, being considered the first line of defence against pathogen and allergen agents. The outer region of the human eye is composed by the cornea, sclera and conjunctiva that provide protection and support to the eye being responsible for the capture and focus of external light onto the retina, which contains photoreceptor cells that convert light into electrical signals to the brain (Barar et al., 2009; Mantelli et al., 2013; Singh et al., 2022).

[0016] The lacrimal functional unit maintains a delicate balance between tear production, distribution, and drainage to sustain ocular surface integrity. The tear film is a complex matrix of water, electrolytes, biological macromolecules, and antimicrobial components that is drained primarily from the main lacrimal gland, with supplementary contributions from the accessory glands of Kraus and glands of Wolfring, located in the conjunctiva section(Conrady et al., 2016; Pflugfelder, 2011). This protects the eye against external agents, while also providing a moist, smooth, and lubricated anterior ocular surface (Conrady et al., 2016; Mantelli et al., 2013; Pflugfelder, 2011; Singh et al., 2022).

[0017] Serving as one of the eye's protective barriers, it is also relevant to emphasize that the corneal epithelium is crucial for preserving cornea's shape and integrity, being the innermost layer of the cornea in direct contact with the aqueous humor in the anterior chamber and responsible for transparency, protection and maintenance of this highly specialized tissue (Barar et al., 2009; Belmonte et al., 2004; Lafreniere and Kelly, 2018; Mantelli et al., 2013; Nag, 2011; Yi et al., 2000).

[0018] Within the corneal epithelium, specialized cell-cell junctions, known as tight junctions, have a key role in the structural integrity of the corneal epithelium by granting intercellular architecture and regulating paracellular transport through biomolecular selective permeability, providing corneal protection and maintenance (Belmonte et al., 2004; Mantelli et al., 2013; Noske et al., 1994; Singh et al., 2022; Yi et al., 2000).

[0019] Studies have demonstrated that the corneal epithelium layer disruption, due to tight junctions dysfunction and degeneration, lead to barrier function impairment, increased susceptibility to infections caused by pathogens and allergens agents with a potential impact on corneal sensitivity, and in the most severe cases significant vision loss (Crespo Millas et al., 2020; Vaidyanathan et al., 2019).

[0020] External and internal triggers such as environmental stress, infections and surgery can lead to a wide range of ocular disease manifestations, including but not limited to dry eye disease (DED), also known as keratoconjunctivitis sicca, that is recognised as a multifactorial condition characterized by the imbalance of the tear film production and homeostasis along with the corneal epithelium impairment that leads to ocular discomfort and disturbances in vision (Andersson et al., 2021; Mantelli et al., 2013; Pflugfelder, 2011; Singh et al., 2022).

[0021] DED, as well as neurotrophic keratitis, may include symptoms such as dry, itchy eyes, a rough or sandy feeling, foreign body sensation, pain or soreness, stabbing or burning, increased intraocular pressure, eye fatigue, congestion, and hypersensitivity. Patients may also experience increased sensitivity to light know as photophobia and blurred vision due to irregularities cornea's shape and integrity. In the worst case, there is a possibility that it may even progress to corneal perforation or loss of vision.

[0022] Zhang Y. et o / .(Zhang et al., 2022) investigated the impact of tear film hyperosmolarity, realizing that tear film hyperosmolarity can cause damage to tight junctions due to increased concentrations of proinflammatory cytokines and other components regarding the inflammatory mechanisms, whereas Andersson J., et al. (Andersson et al., 2021) found that changes in the composition or function of these layers can altered ocular surface microbiota in the corneal epithelium, resulting in the possible entry of pathogen and allergen mediators. The composition of the tear film can lead to increased evaporation or reduced aqueous layers. The change in tear osmolarity and persistent inflammation on the ocular surface led to disease progression.

[0023] While the primary cause of dry eye pathology involves the disruption of tear film maintenance due to lacrimal glands function impairment, recent research has shown that eye inflammation and allergic agents can worsen symptoms and contribute to disease progression leading to chronic inflammatory response (Andersson et al., 2021; Mantelli et al., 2013; Singh et al., 2022). Numerous dermatological conditions, for example Atopic Dermatitis (AD), Rosacea, Blepharitis, and Pruritus localized on or near the eyelids, have been associated with the onset of eye conditions. It is estimated that approximately 50 per cent of patients presenting dry or wrinkled periocular skin conditions may have underlying eye disease. Prompt detection and intervention can prevent disease progression and worsening. The same DED's symptoms can also be found in dermatological conditions mentioned, although they can often be overcome by maintaining a proper periocular skin hygiene and personal care. In the most serious cases, the use of pharmaceutical compositions may be needed.

[0024] When the epithelial barrier is compromised, it allows for increased susceptibility to external pathogens and allergens which can exacerbate symptoms and accelerate disease progression potentially impacting corneal shape and sensitivity, or even impaired vision. This occurs through the initiation of immune responses, leading to an increase in inflammatory mediators on site. These mediators engage in a complex cascade of interactions between pro- inflammatory and anti-inflammatory mediators. The balance between these agents determines the outcome of the disease and it was demonstrated by the research conducted by Singh N., et a / .(Singh et al., 2022). The epithelial barrier dysfunction in ocular allergy was also showed by Mantelli F. et o / .(Mantelli et al., 2013), that explored a new signalling pathway that disrupts the ocular surface barrier and amplifies allergic inflammation.

[0025] The increased adoption of topical molecules in recent years has been growing, due to the fact that it has proven to have more advantages than drawbacks in the efficacy of the pharmaceutical delivery system on the eye. Overall, currently available treatments for dry eye conditions have also been found to be effective by providing relief of symptoms, though longterm treatment, using artificial tears that provide temporary lubrication, whereas corticosteroids and antihistamine eye drops alleviate ocular allergies and allergen-induced inflammation. However, they often fail to address the underlying causes since the management of this condition has evolved beyond the use of tear substitutes and / or inflammation.

[0026] Anti-inflammatory agents, including steroids and non-steroidal compositions, are commonly included in ophthalmic formulations. However, the long-term use of steroid-based compositions has been investigated in the clinical setting to a number of adverse effects. Such effects may include blockage of tear drainage, increased intraocular pressure, optic nerve atrophy and, in the most severe cases, glaucoma blindness. There is a clear need for the research and development of anti-inflammatory formulations that have minimal side effects and are comfortable for patients to use. As our understanding of ocular anatomy and pathology has expanded, so it has the quest for more targeted and refined ophthalmological practices. Thus, the present invention describes a topical delivery of a natural or synthetic THC-based composition isolated or associated with natural or synthetic CBD isolated or associated with other applicable agents as a promising approach to address ophthalmic disease, included but not limited to pathogen and allergen- induced corneal inflammation and ocular surface protection enhancement. A more comprehensive view of the disease landscape could pave the way for the implementation of novel strategies offering dual benefits also for dermatological conditions induced by factors such as sun exposure, stress, and allergies, coupled with emerging cosmetic trends, since they potentially escalate the risk of DED onset and progression.

[0027] Given that ECS can be found in the cornea and eyelids, new possibilities are arising for the potential target delivery of cannabinoid-based formulations in a group of several conditions that affect the cornea and surrounding eye skin. Along with eye protection enhancement, these formulations reestablish tear production homeostasis with the restoration and improvement of the corneal epithelial barrier function, as it will facilitate the adhesion of the eye drops to the ocular surface through the linkage to the ECS receptors, increasing the effectiveness of pharmaceutical delivery.

[0028] In recent years, the effect of cannabinoids in the human ocular tissue have been demonstrated, more exactly in the cornea, playing a key role in including the production of antiinflammatory and antinociceptive effects( Aiello et al., 2020; Nguyen and Wu, 2021; Tran et al., 2022). Evaluation of the bioactive compound retention within inner layer membranes and assessment of potential interactions with the ECS in the corneal epithelium is performed along with the optimization of the formulation delivery strategies to maximize safety and efficacy.

[0029] The CB1R are predominantly located in the corneal epithelium and endothelium, while CB2R has much lesser expressing corneal cells, being identified in the corneal stroma layer, where it can be responsible for activating of aqueous humour turnover(Nguyen and Wu, 2021). Modulating CB2R has immunomodulatory potential, whereas the activation of CB1R appears to play a positive impact in the tight junctions proteins localization in the corneal epithelium.

[0030] Studies shown that although the expression of CBR in cornea and conjunctiva occurs under healthy conditions, the overexpression of these receptors can be modulated by external and internal triggers such as environmental stress, infections and surgery becoming suitable bioactive and pharmaceutical targets (Aiello et al., 2020; Nguyen and Wu, 2021; Tran et al., 2022). Upon induced corneal damage, the ECS is activated not only in the cornea but also in the brain, inducing infiltration of immune cells into the injured tissue and may also be involved in the regulation of cell proliferation (Aiello et al., 2020).

[0031] Despite of the small number of published studies investigating on the correlation between ECS activation and the increase change in tight junctions on tear film homeostasis, studies performed by Cuddihey, H. et o / (Cuddihey et al., 2022). shown that the modulation of ECS through the increase of endocannabinoids molecules in the gastrointestinal tract has a critical role in maintaining intestinal homeostasis being involved in the intestinal membrane permeability, fluid secretion, and immune regulation.

[0032] Furthermore, studies examining the potential link between diabetes and dementia have indicated that the exogenous activation of the cannabinoid system contribute to the expression of tight junction proteins in the Blood-Brain Barrier, thereby promoting cellular structure maintenance and integrity. (Brook et al., 2019).

[0033] Since the corneal epithelium and other epithelium membranes have similar physical and biochemical features associated with present of epithelium cell membrane linked to tight junctions proteins, it can be hypothesized that the corneal epithelium tight junctions could have a mechanism of crosstalk comparable to the one verified in the gastrointestinal tract and in the brain(Brook et al., 2019; Cuddihey et al., 2022; Murataeva et al., 2019; Tran et al., 2022), resulting in tear film production and maintenance.

[0034] Another example of the use of this ophthalmic topical application can be the management or prevention of dry or wrinkled periocular skin, including the eyelids, by targeting the ECS receptors present in the skin tissue around the eye. This topical delivery method has been developed to promote the prevention of dry eye and the hydration of the skin, as well as to provide a cannabinoid antisebostatic, antimicrobial, anti-inflammatory and antioxidant action. Based on the results of all studies performed regarding this topic and all information gathered, it can be concluded that a topical delivery of cannabinoid-based formulations, whether isolated or associated with other applicable agents synergistic agents, including but not limited to steroidal and non-steroidal anti-inflammatory and antihistamines pharmaceutical formulations, as a promising approach in ophthalmic and dermatologic areas. Apart from potential pharmaceutical effects on pain and inflammation(Aiello et al., 2020; Fernandez-Ruiz et al., 2013; Kibret et al., 2022; Nguyen and Wu, 2021; Pagano et al., 2022; Petersen et al., 2023), there are some evidences of the role of cannabinoids in corneal epithelium injuries and re-epithelialization. Tran B., et al. (Tran et al., 2022) shown that the modulation of ECS in mice models through THC-based molecules delivered in eye drops to the corneal site in dry eye disease can protected corneal nerve morphology without changing it, thus maintained corneal sensitivity and reduced infiltration, and leading to tear film balance. Also, Murataeva, N., et o / .(Murataeva et al., 2019) described the potential role of CBR receptors in corneal healing and anti-inflammation process, due to the evidence that this receptors activity is increased in corneal injury and that are required for the normal course of wound closure (Aiello et al., 2020; Murataeva et al., 2019; Nguyen and Wu, 2021; Tran et al., 2022).

[0035] Considering the absence of the prior art, the invented ophthalmic composition includes a natural anti-inflammatory component and a viscosity enhancer, which increases drug retention on the ocular surface, effectively reduces the frequency of administration, and provides relief from inflammatory conditions in the eye and periocular skin.

[0036] SUMMARY OF THE INVENTION

[0037] The most generic embodiment of the present invention describes a topical delivery of a cannabinoid-primary based ophthalmic composition for human use. In another embodiment of the present invention, the formulation further comprises one or more synergistic applicable agents, including but not limited to steroidal and non-steroidal anti-inflammatory and antihistamines pharmaceutical formulations that provide a synergistic effect and address the underlying inflammatory and oxidative biomolecular mechanisms in unhealthy conditions.

[0038] This ophthalmic solution offers a promising approach to reduce pathogen and allergen- induced corneal and ocular surface inflammation and provide protection enhancement in ophthalmic disease, included but not limited to dry eye disease and neurotrophic keratitis, given that these cannabinoid formulations possess anti-inflammatory and antioxidant properties as mentioned above. Another example of the use of this ophthalmic topical application is the management or prevention of dry or wrinkled periocular skin, including the eyelids, with a beneficial outcome for dermatological patient, marking a significant advancement such as in Blepharitis treatments. The use of the present invention as a topical instillation provides a non-invasive technique that involves applying the formulations directly to the target surface, reducing the concentration of molecules that are absorbed into the body and maximizing the desired bioactive response. Since ECS can be found in the corneal membranes and surrounding tissues, the invention takes advantage of the optimized target delivery of a bioactive and pharmaceutical cannabinoid-based formulations in a group of several conditions that affect the cornea.

[0039] The corneal membrane is the primary pathway for ocular penetration, since the absorption of pharmaceutical compositions occur through the anterior segment of the eye and into the aqueous humour, subsequently diffusing to the posterior segment.

[0040] Furthermore, the invention introduces an ophthalmic composition designed to increase the retention time on the ocular surface. The formulation of eye drops is a critical factor in determining their efficacy, particularly in terms of retention time and absorption. One of the methods employed to extend the ocular drug residence time is to enhance the viscosity of the vehicle. A higher viscosity slow down the drainage of the drops from the eye, allowing for a longer period of contact with the ocular surface. This extended retention time significantly improve the absorption of the active ingredients, which is an important benefit for patients.

[0041] For hydrophobic molecules, the creation of a formulation that includes a lipid layer is an advantageous approach. Incorporating a lipid component enables the eye drop to form a small lipophilic layer upon application. This layer help to encapsulate the hydrophobic THC, facilitating its absorption through the lipid-rich environment of the eye.

[0042] The presence of cannabinoid natural-based molecules facilitates the adhesion-adhesion of the topical instillation since it is applied to the ocular surface directly and bond to the ECS receptors present in the corneal epithelial membrane, increasing the effectiveness of formulation product delivery. Increasing the viscosity of the liquid composition prolong the retention of therapeutic agents by providing a gel-like consistency that adheres better to the eye surface and aiding in the effective treatment or prevention of various eye diseases, including retina-related conditions such as Glaucoma and Diabetic retinopathy without visual blur on instillation. The high viscous solvents such as polysorbate and glycerol are also used in the proposed formulation.

[0043] Given that tight junctions in the corneal epithelium play a crucial role in maintaining tear production homeostasis, and that their dysfunction lead to a destabilization of the tear film, which in turn amplifies inflammation, the proposed cannabinoid natural or based-containing formulations are intended to address the underlying inflammatory and oxidative mechanisms of the condition, since both THC and CBD have been shown to have antioxidant and antiinflammatory effects.

[0044] The formulation THC-based improve and restore the function of the corneal epithelial barrier and help reestablish the tear film balance with the improvement and restoration of the intraocular pressure. In another embodiment of the present invention comprises the THC-based molecules combined with a CBD-based solution, which have anti-inflammatory and antioxidant properties. This mitigates inflammation and oxidative stress in the corneal epithelium, thereby enhancing the protection and health of the ocular surface and surrounding skin.

[0045] In another embodiment of the present invention, the formulation further comprises one or more synergistic applicable agents, either natural or synthetic, including but not limited to steroidal and non-steroidal anti-inflammatory and antihistamines pharmaceutical formulations that provide a synergistic effect and address the underlying inflammatory and oxidative biomolecular mechanisms in unhealthy conditions.

[0046] DETAILED DESCRIPTION OF THE INVENTION

[0047] Current ophthalmic formulations fail to meet the fundamental challenges of ophthalmic delivery vehicles for several conditions including included but not limited to dry eye disease, neurotrophic keratitis and Blepharitis. These challenges include improving comfort, minimizing visual blur on instillation, increasing product solubility, increasing molecule retention time and permeation through the corneal structure to achieve a greater intraocular delivery, reducing systemic absorption, and causing minimal local adverse effects.

[0048] The present invention aims to address these challenges and improve the effectiveness of these formulations by introducing new applications for medicinal cannabinoid-based topical products, included but not limited to eyedrops, ophthalmic creams and gels, wipes and sprays for eye and eyelid application.

[0049] The preferred embodiment of the present invention of a cannabinoid-based formulation for the treatment of ocular allergy and inflammation in ophthalmic diseases when topically administered to a human patient.

[0050] In an alternative embodiment, the THC-based composition is combined with a CBD-based composition, for the treatment of ocular diseases and ophthalmic inflammations, including but not limited to pathogen and allergen-induced inflammation in disease context as well as primary prevention and protection. In a further aspect of the present invention, we also provided a method for dermatological condition approach which involves the management and prevention of dry or wrinkled periocular skin associated with ocular diseases.

[0051] 1. MOTHER SOLUTION OF THE INVENTION

[0052] The most generic and preferred embodiment of the present invention includes a method for the treatment of ophthalmic diseases and dermatological conditions, which comprises the use of cannabinoid-containing formulations for topical application in the form of drops, gels, wipe or spray topical compositions.

[0053] The preferred embodiment of invention comprises a THC-based solution, which is either naturally or synthetically obtained. Optionally, said solution include ophthalmic acceptable carriers, such as sterile water or a buffer solution. The THC-based molecules enhance and optimized adhesion, thereby enhancing the performance and effectiveness of the product.

[0054] Our formulations incorporate pharmaceutically acceptable vehicle, either sterile water or a buffer solution as well as carrier solutions for the lipid-soluble compositions proposed with control size distribution, osmolality and pH to enhance product formulation delivery was described on the table below.

[0055] Yet another advantage of said invention is its flexibility for association with various carrier systems, such as nanoparticles, nanomicelles, nanoemulsion, microsphere, emulsions, cyclodextrins or liposomes carrier systems. Each of these systems is characterised by controlled parameters such as particle size distribution, encapsulation efficiency, osmolality, pH and stability.

[0056] Example 1

[0057] In a preferred embodiment, the formulations are prepared at drug concentrations of 0.001 % to 20% THC, further preferably at concentration range of 0.01 % to 5% for THC, the following protocols were employed. The basic formulations of the drug were prepared as followed:

[0058] 1. The requisite quantity of THC for 50 ml was weighed.

[0059] 2. The THC was extracted and dissolved in 5ml of 95% ethanol solution to obtain a clear mother solution.

[0060] 3. The ethanolic solution was then evaporated under vacuum to form a thin film of near-solid matter.

[0061] 4. Deionized water (25 mL) was mixed with octoxynol-40, and the solution was sonicated for approximately 20 minutes to ensure complete formation of mixed micelles.

[0062] 5. The prepared 2x formulations were stored at room temperature.

[0063] In an alternative embodiment, the THC-based formulation further comprises CBD-based molecules, which provide anti-inflammatory and antioxidant properties. CBD-based molecules have the potential to mitigate inflammation and oxidative stress in the corneal epithelium, thereby enhancing the protection and health of the ocular surface. Pharmaceutical acceptable carriers are used for the proper delivery of the ophthalmological formulation also to the surrounding skin of the eye through topical delivery.

[0064] This dual action of the proposed composition could potentially offer a more patientcentric prevention and treatment for ocular and dermatological conditions, reflecting a deep understanding of their needs and comfort, taking quality and safety into consideration.

[0065] Example 2

[0066] Yet another preferred embodiment of the invention considers the formulations at drug concentrations of 0.001% to 20%, with a preferable concentration range of 0.01% to 5% for THC and 0.01% to 2% for CBD. The basic formulations of the drug were prepared as followed:

[0067] 1. The requisite quantity of THC and CBD for 50 ml was weighed.

[0068] 2. The THC and CBD were extracted and dissolved in 5ml of 95% ethanol solution to obtain a clear mother solution.

[0069] 3. The ethanolic solution was then evaporated under vacuum to form a thin film of near-solid matter.

[0070] 4. Deionized water (25 mL) was mixed with octoxynol-40, and the solution was sonicated for approximately 20 minutes to ensure complete formation of mixed micelles.

[0071] 5. The prepared 2x formulations were stored at room temperature.

[0072] In another preferred embodiment of the invention, the formulation further comprises one or more synergistic agents, either natural or synthetic, including but not limited to non-steroidal anti-inflammatory and antihistamines pharmaceutical formulations. Said agents, by increasing the viscosity of the composition, prolong the retention of therapeutic agents, aiding in the effective treatment or prevention of eye diseases.

[0073] Steroid-based formulation are used, although it's important to determine the lowest dose that will produce a clinically meaningful response, due to the potential side effects associated with long-term use of such compounds. Therefore, the benefits and risks must be carefully weighed when considering the use of steroid-based preparations for treatment.

[0074] Optionally, the cannabinoid-based formulation as described is further combined with various excipients such as solvents, stabilizers, or the unique combination with one or more applicable agents that provide a synergistic effect. The required quantity of the composite or bioactive agent varies with factors such as the desired biological outcome, the specific agent (ocular surface or periocular skin), the composition of the encapsulating matrix, and the target tissue. 2. CANNABINOID-BASED PRODUCTS COMPOSITION

[0075] The ideal topical formulation is a delicate balance of efficacy, safety, and comfort. It should contain active ingredients that effectively treats the condition it is designed for, such as lubricants for dry eyes and eyelids, antihistamines for allergies, or anti-inflammatory agents for the inflammatory mediators on site. The concentration of the active ingredient should be optimized to provide bioactive effects while minimizing potential side effects.

[0076] In addition, the formulation must consider both physical and chemical characteristics. These include pH and osmolarity, which should closely mirror the natural tear film. The tonicity should be comparable to a 0.9% NaCI solution or isotonic. Additionally, the formulation include buffering agents to guarantee an optimal pH stability range of 6.5 to 10.

[0077] The clarity of the eye solutions and uniformity of the ointments and suspensions are also controlled to prevent stinging or burning upon application in case of the eyedrops and eye gel. The clarity of eye solutions is controlled by proper filtration and sterilization, to ensure that the solution is free from particulate matter and microbial contamination, while the uniformity of ointments and suspensions is controlled by thorough mixing during the manufacturing process or even the use of carrier systems that include nanoparticles, nanomicelles, nanoemulsion, microsphere, emulsions, cyclodextrins or liposomes carrier systems.

[0078] The ensurance of the stability and sterility of the ophthalmologic topical formulations proposed are of prime importance to safeguard eye health and preventing unwanted side effects. Therefore, stability studies are preformed to ensure that the cannabinoid-based formulations stay effective and safe under various conditions such as temperature, humidity, and light.

[0079] The viscosity of ophthalmologic formulations, such as eye gels, are controlled by the selection and concentration of polymers used in the formulation. High molecular weight polymers like hydroxypropyl methylcellulose (HPMC) or carboxymethylcellulose (CMC) are used to increase viscosity. The concentration is optimized to ensure the formulation is viscous enough to prolong contact time with the eye surface, but not so high as to blur or impair vision.

[0080] Our formulations incorporate pharmaceutically acceptable vehicle, either sterile water or a buffer solution as well as carrier solutions for the lipid-soluble compositions proposed with control size distribution, osmolality and pH to enhance product formulation delivery. The formulation scale from mother solution into the final product with proper pharmaceutically acceptable vehicle to guarantee efficacy and safety of the product, including but not limited to drops, gels, wipe or spray topical compositions.

[0081] • Eye Drops provides pharmaceutical and / or bioactive properties as well as soothing relief for corneal inflammation and allergen irritation comprising the mother solution and isotonic sodium chloride solution, boric acid solution, phosphate buffered saline (PBS), dulbecco's phosphate buffered saline (DPBS) with calcium and magnesium, and hanks' balanced salt solution (HBSS) and other proper pharmaceutically acceptable vehicles. If needed, viscosity agents will allow greater contact time with the eye's surface, such as Hydroxyethyl cellulose, Hydroxypropyl cellulose, Methylcellulose, Polyvinyl alcohol and Polyvinylpyrrolidone, although THC and CBD provide adherence to the corneal membranes and tissues by interaction with ECS receptors.

[0082] Due to the hydrophobic nature of cannabinoids, the introduction of a carrier system significantly enhance this process being essential for the effective delivery of these therapeutic compounds. Carriers such as nanoparticles, nanomicelles, nanoemulsions, microspheres, emulsions, cyclodextrins, or liposomes encapsulate the cannabinoids, improving their dispersibility and solubility in the aqueous solution.

[0083] • Eye Gel offers long-lasting lubrication and are presented in drop form or ointment form being the easiest way of application for most patients. Given the low solubility of cannabinoid molecules, the most stable form is ointment rather than an aqueous vehicle, which will include but not limit to sodium hydroxide, carbomer, disodium edetate Purified water is also used with proper carrier system mentioned above.

[0084] • Eyelid Wipe, Scrub, Foam or Cleanser helps in cleaning and refreshing the eyelids and lashes in disease context and / or during skin care routine. Sodium chloride, potassium chloride, calcium chloride dihydrate, magnesium chloride hexahydrate, sodium acetate, sodium citrate dihydrate, hyaluronic acid and purified water is used as pharmaceutical vehicles to proper delivery the ophthalmological formulation to the surrounding skin of the eye through topical delivery. Octoxynol and Vitamin E are also used as emulsifying agents, cleansing agents, and solubilizers for lipid-soluble cannabinoid molecules present in the mother solution.

[0085] • and Eyelid Spray that provides a quick and easy solution for eyelid hygiene as well as moisturizing effect using a comprising formulation of sodium chloride, purified water, ethanol, phenoxyethanol as pharmaceutical vehicles to proper application in the eyelids and topical delivery to the eye and surrounding skin. Octoxynol, Vitamin A and E are used as emulsifying and cleansing agents, as well as solubilizers for cannabinoid-based mother solution.

[0086]

[0087] 3. METHOD OF APPLICATION

[0088] The application method for eye and periocular skin treatments and healthcare has been defined with a patient-centric approach. It is suitable for patients with sensitive eyes or discomfort with direct application. This design ensures effective delivery and enhances patient comfort and compliance.

[0089] Eye Drops: Administer 1-2 drops directly into the eye using a dropper. Ensure the solution is sterile and isotonic. Blink to distribute the drops evenly.

[0090] Eye Gels: Pull the lower eyelid down and squeeze a small strip of gel into the pocket. Close eyes and move the eyeballs to spread the gel.

[0091] Eyelid Wipe, Scrub, Foam or Cleanser: Used for cleaning and moisturizing the eyelids and surrounding skin. Gently wipe from the inner corner of the eye outwards, using a fresh wipe for each eye.

[0092] Eye Sprays: Spray once or twice a few inches away from the closed eyelid. Allow the mist to settle and penetrate the eyelid surface and eyelashes. Ideal for sensitive eyes or those who find direct application methods uncomfortable, and also to remove debris or makeup residue, while applying a moisturizing solution that helps with dry periocular skin. 4. DESCRIPTION OF THE MANUFACTURING PROCESSES AND QUALITY TESTING FOR CANNABINOID-BASED TOPICAL DELIVERED FORMULATIONS

[0093] 4.1 1. MANUFACTURING PROCESS FOR CANNABINOID-BASED EYE DROPS FOR TOPICAL DELIVERY

[0094] The manufacturing of cannabinoid-based eye drops comprises several critical steps designed to ensure the stability, efficacy, and safety of the final product. Initially, high- purity cannabinoid extracts, including THC isolated or associated with CBD and potentially other cannabinoids, are dissolved in a carrier oil suitable for ophthalmic use, such as medium-chain triglyceride (MCT) oil, as well as other carriers such as Octoxynol, Vitamin A and E.

[0095] MCT enhance the solubility and facilitate ocular absorption of poorly soluble active pharmaceutical ingredients within the tear fluid, thereby increasing their bioavailability. Factors such as viscosity and particle size have a significant impact on ocular drug absorption. Consequently, optimising these factors in eye drop formulations using MCT result in enhanced pharmaceutical outcomes.

[0096] Subsequently, the oil base is emulsified with an aqueous phase that has been preconditioned with buffering agents, isotonicity adjusters such as sodium chloride or potassium chloride, and viscosity enhancers such as hyaluronic acid or carboxymethylcellulose. This process enhances the retention time on the ocular surface. The use of an advanced high-shear homogenisation technique ensures the formation of a nanoemulsion with very small droplet sizes. This maximises bioavailability and reduces eye irritation and corneal disruption.

[0097] The pharmaceutical Carriers such as nanoparticles, nanomicelles, nanoemulsions, microspheres, emulsions, cyclodextrins, or liposomes encapsulate the cannabinoids- based formulations, and improve their dispersibility and solubility in the aqueous solution.

[0098] Each batch is subjected to a series of rigorous in-process quality testing, including pH balance, osmolarity, sterility, and particle size distribution. Filtration of all compounded eye drop solutions using a 5 pm filter to remove any visible particulate matter. Ensuring the pH of eye drops is within the range pH 6.5 to 10. Use a suitable buffer, defined according to the intended final product to control and maintain the pH during storage. The tonicity of the eye drops need to be similar to natural tears. Acceptable range is 0.5- 2% saline tonicity.

[0099] According to the stability of the cannabinoid-based molecules isolated or associated with one or more applicable agents at high temperature, two possible methods as follow:

[0100] - Autoclaving: Sterilise the final product stable at high temperature using autoclaving (saturated steam at 121-132°C) for 15 minutes.

[0101] - Filter sterilisation: Sterilise the solution by filtration through a 0.22 pm filter into a sterile final container under aseptic conditions.

[0102] The final product is then filled into aseptically sterilized, single-dose containers, which are suitable for the product and have tamper-evident seals. This process ensures the safety of the patient and the integrity of the product during distribution and storage.

[0103] Quality control (QC) testing for cannabinoid-based eye drops involves a series of stringent tests to ensure product safety, efficacy, and consistency according to the quality requirements of medical devices. The testing includes:

[0104] - Sterility Testing: Conducted to ensure no microbial contamination throughout the product's shelf life.

[0105] - pH and Osmolality Testing: Critical for ensuring the product's comfort and safety upon ocular application. The pH is maintained within a physiologically acceptable range (typically 6.5 to 10), and osmolality is adjusted to be isotonic with human tears (280-300 mOsm / kg).

[0106] - Cannabinoid Concentration and Stability Testing: Utilizing High-Performance Liquid Chromatography (HPLC) to verify the concentration of cannabinoids and ensure their stability over time, under various storage conditions.

[0107] - Particulate Matter Testing: Ensuring the solution is free from particulate matter using light obscuration particle count test.

[0108] - Preservative Efficacy Test: Conducted to confirm the effectiveness of the antimicrobial preservatives included in the formulation.

[0109] 4.2. MANUFACTURING PROCESS FOR CANNABINOID-BASED EYE GEL FOR TOPICAL DELIVERY Eye gel formulation begins with the preparation of a semi-synthetic polymer-based hydrogel, which acts as the primary gel matrix of the proposed. This polymer is preconditioned in a solvent system to achieve most advantageous swelling properties, such as high-water retention and rapid gelation, and is selected for its biocompatibility, since the polymer-based hydrogel used do not cause any irritation or harm to the eye tissues, and mucoadhesive properties as it is applied as solution that rapidly transit to gel increasing the adherence to the corneal surface.

[0110] The cannabinoid-based formulations are incorporated into the gel under controlled conditions, which involves maintaining specific parameters such as temperature, pressure, and humidity within specific range. These conditions are rigorously monitored and adjusted as necessary to guarantee the stability and integrity of the cannabinoids. The process employs cold processing techniques to prevent the degradation of the cannabinoids.

[0111] Although the formulation is stable on its own, stabilisers and antioxidants are added to the formulation to protect the cannabinoids from oxidative degradation. Oxidative degradation lead to a loss of potency of the cannabinoids-based formulation, which are the key active ingredients. Maintaining the integrity of these cannabinoids is essential for the pharmaceutical efficacy of the product throughout its shelf life.

[0112] The gel is homogenised using ultrasonic mixing to ensure uniform distribution of cannabinoids throughout the gel matrix. The gel is filled into an applicator and other type of suitable containers under nitrogen to avoid exposure to oxygen, thus preserving the integrity of the cannabinoids-based topical compositions since THC and CBD molecules suffer oxidation. Each applicator is then sealed with a child-resistant closure to ensure safety and regulatory compliance.

[0113] The QC for eye gels includes specific tests tailored to gel formulations, focusing on both physical and chemical stability:

[0114] - Viscosity Measurement: The ensurance of the gel's consistency is suitable for easy application and sufficient ocular surface contact time.

[0115] - Sterility and Endotoxin Testing: The verification of the absence of microbial and endotoxin contamination, critical for products in contact with the eye. - Rheological Properties Testing: The Assess of the gel's structural integrity and performance under stress and different environmental conditions.

[0116] - Cannabinoid Potency and Homogeneity Tests: The use of HPLC and uniformity testing to ensure each batch contains a uniform distribution of cannabinoids at the specified potency.

[0117] - Antioxidant Efficiency Testing: The evaluation of the effectiveness of antioxidants in the formula to protect the cannabinoids from oxidative degradation.

[0118] 4.3 MANUFACTURING PROCESS FOR CANNABINOID-BASED EYE WIPES

[0119] The manufacture of cannabinoid eye wipes involves the saturation of hypoallergenic, biodegradable non-woven pads with the cannabinoid-containing mother solution described in section 1. This formulation comprises the following chloride, potassium chloride, calcium chloride dihydrate, magnesium chloride hexahydrate, sodium acetate, sodium citrate dihydrate, hyaluronic acid, rosmarinic acid, purified water, along other pharmaceutical acceptable carriers such as Octoxynol, Vitamin A and E that are used as emulsifying and cleansing agents, as well as solubilizers for cannabinoid-based mother solution through topical delivery to the surrounding skin of the eye.

[0120] The first step in the process is to dissolve the selected mother solution cannabinoid-based in a combination of skin-compatible hydrosols and a mild preservative system to ensure microbial integrity without irritation to the surrounding eye tissues. Hyaluronic acid, rosmarinic acid and aloe vera are added to enhance the moisturising effect, creating a soothing matrix that also facilitates the delivery of pharmaceutical composition by topical delivery.

[0121] Each hypoallergenic, biodegradable non-woven pad is then evenly saturated using an wet wipes automatic equipment that ensures precise control over the amount of solution absorbed by each wipe. This process is critical in enabling consistent dosing, an important aspect of medical accuracy and patient safety.

[0122] After saturation, the wipes are transferred to a laminar flow packaging area where each pad is individually sealed in a nitrogen flushed, aluminium-lined pouch. The use of nitrogen not only protects the cannabinoids from oxidation, but also ensures that the wipes remain moist and effective until the moment of use. The packaging is specifically designed with a resealable label to maintain product integrity between uses or it is packaged in individual doses also.

[0123] The eye wipes undergo a series of quality testing designed to ensure product safety and functionality, especially focusing on:

[0124] - Content Uniformity Testing: Each wipe consistently delivers the same amount of cannabinoid-infused solution.

[0125] - Microbial Contamination Testing: Each batch of wipes is sterile, using microbial enumeration and specified microorganisms tests.

[0126] - Preservation and Stability Testing: The stability of the solution on the wipes under accelerated aging conditions to verify the long-term stability of cannabinoids.

[0127] - Skin Irritation Testing: The wipes are hypoallergenic and safe for use on sensitive skin around the eyes.

[0128] 4.4 MANUFACTURING PROCESS FOR CANNABINOID-BASED EYE SPRAY

[0129] The cannabinoid-based eye spray is manufactured comprising pharmaceutically acceptable vehicle, either sterile aqueous base solution or a buffer solution as well as nanoparticles, nanomicelles, nanoemulsion, microsphere, emulsions, cyclodextrins or liposomes carrier systems with control size distribution, osmolality and pH containing cannabinoid-mother formulation solubilised. This advanced formulation approach uses ocular compatible surfactants to ensure that the cannabinoids remain in a soluble, bioavailable form. Glycerin and panthenol are included to enhance absorption and prolong the soothing effect on dry eyes and eyelids.

[0130] The solution is processed by high-pressure homogenisation to reduce the particle size, which is essential to produce a fine, consistent mist that evenly cover the ocular surface without causing irritation. This step also ensures the stability of the solution.

[0131] For the eye spray, QC focuses on ensuring the aerosol delivery system's performance and the formulation's stability:

[0132] - Droplet Size Distribution Testing: The spray produces a consistent and appropriate droplet size, which is crucial for safety and efficacy in delivering cannabinoids to the eye's surface. - Spray Pattern: The characteristics of the spray emitted from the dispenser to ensure comprehensive coverage of the ocular surface.

[0133] - Sterility and Preservative Efficacy Tests: Similar to eye drops, confirming no microbial growth and the effectiveness of preservatives.

[0134] - Cannabinoid Stability and Homogeneity Testing: Using HPLC to ensure the cannabinoids remain stable and evenly distributed throughout the product lifecycle.

[0135] The formulation contains THC-based molecules, either natural or synthetic, used alone or in combination with natural or synthetic CBD and other synergistic agents that enhance therapeutic effects and promote ocular surface and periocular skin protection. These agents with known anti-inflammatory and antioxidative properties are included to enhance the formulation's pharmaceutical response and to meet the specific needs of patients with ocular conditions.

[0136] The following are considered among others also used: Alpha Lipoic Acid, Reduced Glutathione, CoQlO, Superoxide Dismutase, octoxynol, Vitamin A and E, Pycnogenol, Lutein- derivatives, Flavonoids, Beta-Carotene, Beta-Cryptoxanthin, Diclofenac, NSAIDs, Cox2 inhibitors and Ginkgo Biloba. Additional agents like Zeaxanthin, Omega-3 Fatty Acids, Taurine, N- Acetylcysteine, Resveratrol, Curcumin, Hyaluronic Acid, Rosmarinic Acid, Tea-tree oil, Caffeine and Green Tea Extract are also used. These agents, both synthetic and natural, enhance the bioactive efficacy of the innovative products described by ensuring solubility and facilitating ocular and eyelids absorption, leading to improved patient outcomes in context of eye disease and dermatological conditions.

[0137] The proposed formulations is applied directly to the surface of the eye using a dropper, spray, towel, cream, lotion, gel, paste, iontophoresis or applicator, being designed to be absorbed through the corneal membranes and tissues by binding to the suitable CBR, delivering the cannabinoids-based compositions directly to the pharmaceutical target area.

[0138] The exact dosage and frequency of application vary depending on the specific condition being treated and should be supervised by a healthcare professional. The patient should clean the area of application before applying the formulation to ensure optimal absorption. REFERENCES

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Claims

Claims1 . The use of a THC-containing solution for the manufacture of ophthalmic formulations and products for the treatment of ocular allergy and inflammation in ophthalmic diseases when topically administered to a human patient .2 . The use as claimed in Claim 1 , wherein the ocular allergies include dry eye disease, neurotrophic keratitis and periocular dermatitis .3 . The use as claimed in Claim 1 , wherein the ophthalmic diseases include dry periocular skin and eyelids along with corneal protection .4 . A cannabinoid-based formulation for ocular allergy and inflammation in ophthalmic diseases treatment comprising the use THC-based molecules .5 . The cannabinoid-based formulation of Claim 1 further comprising the used of CBD-based molecules .

6. The cannabinoid-based formulation of Claims 1 and 2 further comprising one or more synergistic agents , including but not limited to non-steroidal anti-inflammatory and antihistamines pharmaceutical formulations .7 . The cannabinoid -based formulation of Claim 3 wherein the viscosity of the composition range from 10-300 mPas with an optimal viscosity of 30-250 mPas .8 . A method for manufacturing cannabinoid-based ophthalmic solutions , comprising :- Dissolving high-purity cannabinoid extracts , including THC and / or CBD, in a carrier oil suitable for ophthalmic use, selected from the group consisting of medium-chain triglyceride (MCT) oil, Octoxynol, Vitamin A, and Vitamin E .- Enhancing the solubility and ocular absorption of the cannabinoid-based solution by incorporating MCT oil , thereby improving the bioavailability of the active pharmaceutical ingredients .- Optimizing the viscosity and particle size of the formulation to enhance ocular drug absorption and therapeutic efficacy, wherein the viscosity of the composition range from 10-300 mPas with an optimal viscosity of 30-250 mPas , and particle size as below :THC-based particle size THC and CBD-based particle sizeLiposomes : 50-100 nmEmulsions : 200-300 nmNanoparticles : 300-900 nm Liposomes : 50-200 nmEmulsions : 200-400 nmNanoparticles : 300-950 nm- Emulsifying the oil-based cannabinoid solution with an aqueous phase, preconditioned with buffering agents , isotonicity adjusters , and viscosity enhancers , to increase the retention time on the ocular surface .- Forming a nanoemulsion with small droplet sizes ( ranging from 50 to 950 nm) using a high-shear homogenization technique, thereby maximizing bioavailability and minimizing ocular irritation .- Encapsulating the cannabinoid formulation within pharmaceutical carriers selected from the group consisting of nanoparticles , nanomicelles , nanoemulsions , microspheres , emulsions , cyclodextrins , or liposomes to improve dispersibility and solubility in the aqueous phase .- Filtering the solution using a 5 pm filter to remove particulate matter, and maintaining the pH within a range of 6 . 5 to 10 using an appropriate buffer system, with the tonicity adjusted to a range of 0 . 5% to 2% saline .- Sterilizing the final product through a method selected from the group consisting of : o Autoclaving at temperatures between 121-132 ° C for 15 minutes . o Filter sterilization through a 0 . 22 pm filter under aseptic conditions .- Filling the sterilized solution into aseptically sterilized, single-dose containers with tamper-evident seals to ensure product safety and integrity during distribution and storage .- Conducting quality control tests on the final product , including :o Sterility testing to ensure the absence of microbial contamination . o pH and osmolality testing to maintain physiological compatibility . o Cannabinoid concentration and stability testing using High-Performance Liquid Chromatography (HPLC) . o Particulate matter testing to confirm the absence of visible particles . o Preservative efficacy testing to verify the effectiveness of antimicrobial preservatives .9 . A method for formulating a cannabinoid-based eye gel, comprising :- Preparing a semi-synthetic polymer-based hydrogel, preconditioned in a solvent system to achieve optimal swelling properties , selected for its biocompatibility and mucoadhesive properties to ensure rapid transition to a gel upon application and adherence to the corneal surface .- Incorporating cannabinoid-based formulations into the hydrogel matrix under controlled conditions , including specific temperature, pressure, and humidity ranges , to maintain the stability and integrity of the cannabinoids , employing cold processing techniques to prevent cannabinoid degradation .- Optionally adding stabilizers and antioxidants to the formulation to protect the cannabinoids from oxidative degradation, thereby maintaining the pharmaceutical efficacy of the product throughout its shelf life .- Homogenizing the gel using ultrasonic mixing to ensure uniform distribution of cannabinoids within the gel matrix .- Filling the gel into applicators or suitable containers under a nitrogen atmosphere to prevent exposure to oxygen, preserving the integrity of the cannabinoid-based composition .- Sealing each applicator with a child-resistant closure to ensure safety and compliance with regulatory standards .- Performing quality control tests specific to the eye gel formulation, including :o Viscosity measurement to ensure appropriate consistency for easy application and adequate ocular surface contact time . o Sterility and endotoxin testing to confirm the absence of microbial and endotoxin contamination . o Rheological properties testing to assess the gel ' s structural integrity and performance under varying environmental conditions . o Cannabinoid potency and homogeneity tests using High- Performance Liquid Chromatography (HPLC) to ensure uniform distribution and specified potency of cannabinoids . o Antioxidant efficiency testing to evaluate the effectiveness of antioxidants in protecting cannabinoids from oxidative degradation .10 . A method for manufacturing cannabinoid-infused eye wipes , comprising :- Saturating hypoallergenic, biodegradable non-woven pads with a cannabinoid-containing mother solution, the solution including chloride, potassium chloride, calcium chloride dihydrate, magnesium chloride hexahydrate, sodium acetate, sodium citrate dihydrate, hyaluronic acid, rosmarinic acid, purified water, and pharmaceutically acceptable carriers such as Octoxynol, Vitamin A, and Vitamin E .- Dissolving the cannabinoid-containing solution in a mixture of skin-compatible hydrosols and a mild preservative system to maintain microbial integrity while preventing irritation to the skin around the eyes , selected from the group consisting of Alpha Lipoic Acid, Reduced Glutathione, CoQl O , Superoxide Dismutase, Octoxynol, Vitamin A, Vitamin E, Pycnogenol, Lutein derivatives , Flavonoids , BetaCarotene, Beta-Cryptoxanthin, Diclofenac, NSAIDs , Cox2 inhibitors , Ginkgo Biloba, Zeaxanthin, Omega-3 Fatty Acids , Taurine, N-Acetylcysteine, Resveratrol, Curcumin, Hyaluronic Acid, Rosmarinic Acid, Tea-tree oil, Caffeine, and Green Tea Extract .- Enhancing the moisturizing effect of the wipes by incorporating hyaluronic acid, rosmarinic acid, and aloe vera into the solution .- Saturating each non-woven pad evenly using an automatic wet wipes production line equipment , ensuring precisecontrol over the amount of solution absorbed by each wipe to achieve consistent dosing .- Conducting quality control tests on the eye wipes , including : o Content uniformity testing to confirm that each wipe delivers a consistent amount of cannabinoid-infused solution . o Microbial contamination testing to ensure sterility through microbial enumeration and specified microorganisms tests . o Preservation and stability testing to verify the longterm stability of cannabinoids under accelerated aging conditions . o Skin irritation testing to confirm that the wipes are hypoallergenic and safe for use on sensitive skin around the eyes .11 . A method for manufacturing a cannabinoid-based eye spray, comprising :- Preparing a pharmaceutically acceptable vehicle, selected from the group consisting of sterile aqueous base solution or a buffer solution, and incorporating a carrier system selected from the group consisting of nanoparticles , nanomicelles , nanoemulsions , microspheres , emulsions , cyclodextrins , or liposomes , wherein the carrier system has controlled size distribution, osmolality, and pH, and is solubilized with a cannabinoid-mother formulation .- Utilizing ocular-compatible surfactants to maintain cannabinoids in a soluble and bioavailable form within the formulation . Glycerin and panthenol are included to enhance absorption and prolong the soothing effect on dry eyes and eyelids .- Incorporating glycerin and panthenol to enhance absorption and prolong the soothing effect on dry eyes and eyelids .- Processing the solution by high-pressure homogenization to reduce particle size ( ranging from 50 to 950 nm) , thereby producing a fine, consistent mist that evenly covers the ocular surface without causing irritation, and ensuring the stability of the solution .- Conducting quality control tests on the eye spray formulation, including : o Droplet size distribution testing to ensure the spray produces a consistent and appropriate droplet size for safe and effective delivery of cannabinoids to the eye ' s surface . o Spray pattern testing to ensure comprehensive coverage of the ocular surface . o Sterility and preservative efficacy tests to confirm the absence of microbial growth and the effectiveness of preservatives . o Cannabinoid stability and homogeneity testing using High-Performance Liquid Chromatography (HPLC) to ensure cannabinoids remain stable and evenly distributed throughout the product lifecycle .- Formulating the eye spray to include the cannabinoid- based solution and other synergistic agents selected from the group consisting of Alpha Lipoic Acid, Reduced Glutathione, CoQl O , Superoxide Dismutase, Octoxynol, Vitamin A, Vitamin E, Pycnogenol, Lutein derivatives , Flavonoids , Beta-Carotene, Beta-Cryptoxanthin, Diclofenac, NSAIDs , Cox2 inhibitors , Ginkgo Biloba, Zeaxanthin, Omega-3 Fatty Acids , Taurine, N-Acetylcysteine, Resveratrol, Curcumin, Hyaluronic Acid, Rosmarinic Acid, Tea-tree oil, Caffeine, and Green Tea Extract .

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