Intraocular iontophoretic delivery of a cannabinoid-based formulation, associated with other agents for neuroprotection in ophthalmic conditions

Abstract

The present invention relates to the medical device and ophthalmological industry, as well as related fields such as dermatology and cosmetics, since the formulation includes natural neuroprotective components. The invention describes an iontophoretic delivery of cannabinoid-based formulations designed for ophthalmic conditions, that comprise pharmaceutically acceptable charged vehicles, including but not limited to cationic surfactants, cyclodextrins, nanoparticles and microspheres, emulsions or liposomes, with control the size distribution, potential, osmolality and pH. In a further embodiment of the invention, the intraocular composition proposed further comprises one or more synergistic agents, including but not limited to neuropeptides, exosomes, mitochondrial-derived peptides, complement inhibitors, senolytics, autophagy enhancers, antioxidants, saffron, and non-steroidal anti-inflammatory pharmaceutical drugs with pharmaceutically acceptable charged vehicle.

Description

[0001] DESCRIPTION INTRAOCULAR IONTOPHORETIC DELIVERY OF A CANNABINOID-BASED FORMULATION FOR NEUROPROTECTION IN OPHTHALMIC CONTDIIONS FIELD OF INNOVATION The invention relates to the medical device andophthalmological industry, as well as related field s such asdermatology and cosmetics, since the formulation in cludesnaturalneuroprotective components. The main embodiment present invention describes anintraocular delivery of a cannabinoid-based ophthal miccomposition that includes tetrahydrocannabinol (THC )-basedmolecule. In a preferential embodiment of the inven tion, theTHC-based molecule is combined with cannabidiol (CB D) inpharmaceutically acceptable charged vehicles, inclu ding butnot limited to cationic surfactants, cyclodextrins,nanoparticles and microspheres, emulsions or liposo mes, withcontrol the size distribution, potential, osmolalit y and pH.In another embodiment of the preferred invention, t heintraocular composition proposed further comprises one or more synergistic agents, including but not limited toneuropeptides, exosomes, mitochondrial-derived pept ides,complement inhibitors, senolytics, autophagy enhanc ers,antioxidants, saffron, and non-steroidal anti-infla mmatoryformulations with pharmaceutically acceptable charg edvehicle.Such ophthalmic solution is adapted to be delivered using aniontophoretic method. Another example of the use of thisophthalmic application, in addition to delaying theprogression of glaucoma, age-related macular degene ration(AMD) and diabetic retinopathy (DR), is the potenti alneuroprotective effect to preserve the retina in oc ularpathologies such as neuroretinal degeneration by pr eventingor delaying neuronal cell death and maintaining neu ronalfunction after an initial insult, thus avoiding los s ofvision.In another embodiment of the present invention, theformulation further comprises one or more synergist icapplicable agents, either natural or synthetic, inc ludingbut not limited to neuropeptides, exosomes, mitocho ndrial-derived peptides, complement inhibitors, senolytics ,autophagy enhancers, antioxidants, saffron, and non -steroidal anti-inflammatory formulations that provi de asynergistic effect and address the underlying infla mmatoryand oxidative biomolecular mechanisms in unhealthy conditions.As cannabinoid-based formulations, it will have aff inity tothe receptors of the endocannabinoid system (ECS) p resent inthe biomolecular membranes and structures of the hu man eye.Whilethemainfocuswillbetheretinalbarriersa ndretinaloptical nerve, it is important to consider that the compoundmusttraverse various multi-layered barriers.As a result,theremaybesmallretentionofthemoleculewithin theinnerlayermembranesdue to the presence ofECS. In parallel,the cannabinoid-based composition can also beformulated to be applied to the eyelid for the assi stanceand prevention of symptoms of periocular skin and e yelidsconditions / procedures along with corneal protection . It canbe considered the latest innovation in the dermatol ogicalfield, including but not limited for the achievemen t ofshort-term superficial protection of eyelid skin du ringmedical procedures and surgery, as CBD as analgesic musclerelaxant, neuroprotective and antioxidant propertie s. Thismethod of application can also be used for long-ter m healthcare alternative, where the patient is not comforta ble withotheroptions,similarto intravitreal injectionap proaches.

[0002] BACKGROUND In ophthalmology, the delivery of therapeutic molec ulesto the posterior segment of the eye represents a si gnificantchallenge, primarily due to the complex anatomy andphysiology of the eye. Anatomical barriers have a d irectimpact on the efficacy and bioavailability of pharm aceuticalformulations, making it essential to have a compreh ensiveunderstanding of biomolecular mechanisms to developeffectiveconditionmanagementoptions.Furthermore ,currentstrategies use intravitrealand periocular routes, whichoften result in patient discomfort and pose substan tialcompliance issues due to the invasive nature of the methods.The need for a less invasive and cost-effective met hodof administration in ophthalmology led to the devel opment ofour cannabinoid-based composition. It is patient-ce ntred,designed for the first use of natural cannabinoid o r basedmolecules administered by iontophoresis. This inven tionaddresses the challenges described above and provid es aninnovative solution, reflecting the needs and comfo rt ofpatients. Iontophoresis is a non-invasive technique that prom otesthe diffusion of pharmacological molecules acrossf unctionalbarriersapplyingasmallphysicalforceofanelec tricfieldto enhance the diffusion of the molecules through e yebarriers and membranes (Shoeibi et al.,2014; Wang et al., 2021; Wei et al., 2023).This method was found to be safeand effective for the intraocular delivery of canna binoid-based compositionsto the posteriorsegmentofthe eye. The principle of iontophoresis is based on the basi celectrical principle that oppositely charged ions a ttractand same charged ions repel, enhancing the drug tra nsportacross biological the barriers and membranes that c omposethe eye, applying direct-field effect, also known as theNernst-Planck effect, that is based on the principl e of ionmovement caused by an applied electrical potential gradient(Shoeibi et al.,2014; Wang et al., 2021; Wei et al., 2023).The motion of the solvent can enhance the transport of ionicand when dealing with neutral molecules, the electr ic fielddoes not cause any charge separation, and therefore does notaffect their transport (Shoeibi et al.,2014; Wang et al.,2021; Wei et al., 2023). There are a few current iontophoretic methods inophthalmology that demonstrate the potential for fu rtherapplications: -OcuPhor®: an iontophoretic system designed to deliv erdexamethasone, an anti-inflammatory corticosteroid, tothe eye's posteriorsegment.Ithas shown efficacy in treating uveitis and macular edema by delivering th edrug directly to the retina, bypassing the need forinvasive injections. -Visulex®: Another iontophoretic system used to deli verantibioticsandcorticosteroidstotheeye.Ithas been investigated for the treatment of bacterial keratit isby delivering a high concentration of antibiotics directly to the cornea, avoiding systemic side effects.. - EyeGate® II Delivery System: Used to deliver therapeuticagentssuch asdexamethasone phosphate and other anti-inflammatory drugs, it has been tested i nthe treatment of dry eye syndrome and post-surgicalinflammation,showing potentialto reduce the need for frequenteye dropsorinjections. Some of the advantages of iontophoretic administrat ioninclude its ability to provide a more effective and targeteddelivery of molecules by delivering a high concentr ation of pharmaceutical formulations into both the anterior andposterior segments of the eye, or being a non-invas ivealternative to intravitreal injections, which are c urrentlythe most common method for delivering pharmaceutica lcompositions to theposterior segmentof theeye (Lee et al.,2017; Saraiva et al., 2023; Tahir et al., 2021; Wang et al., 2021; Wei et al., 2023). Our product offers a more comprehensive solution th anexisting iontophoretic systems, such as OcuPhor®, V isulex®,andEyeGate®II,byaddressinglimitationsthatthe sesystemsare unable to fully overcome. While these systems a reeffective in delivering corticosteroids and antibio tics,theyarelimitedtospecifictherapeuticareas,suc hasanti-inflammatory or infection treatment. In contrast, o urcannabinoid-based formulation, delivered via iontop horesis,offers neuroprotective, anti-inflammatory and antio xidantbenefits, making it a versatile solution for a wide r rangeof ocular conditions, including retinal neurodegene ration.In addition, our product improves patient comfort b yproviding a non-invasive, targeted solution for bot h theanterior and posterior segments, while improving bioavailability and reducing the need for frequent or invasive administration methods. Emerging neuroprotective strategy was explored to conserve the retina in ophthalmic pathologies such as neuroretinaldegeneration.Infact,theeyecanbe considereda tool for the early diagnosis of Alzheimer's and o therneurodegenerative diseases through ocular manifesta tions.The neuroprotection of retina is a defending mechan ismdesigned to prevent or delay neuronal cell death, a nd tomaintain neural function following an initial insul t.The delivery of formulations to the posterior segme nt ofthe eye remains a significant challenge in the mana gement ofocular conditions. Traditional methods, such as top ical eyedrops and systemic administration, are often ineffe ctive dueto the complex anatomy and the limitations of the o cularbarriers protective mechanisms, including the tear film,corneal, vitreous, haematoretinal, and haemoaqueousbarriers, significantly obstruct the delivery parti cularlyto the retina (Barar et al., 2009; Duraikkannu andChatterjee, 2022; Garzone et al., 2023; Laihia et al., 2020; Spadoni et al., 2017; Lee et al., 2017; Saraiva et al., 2023; Tahir et al., 2021; Wang et al., 2021; Wei et al., 2023) . SUMMARY OF THE INVENTION The present invention describes an iontophoreticdelivery of cannabinoid-based formulations designed forophthalmic conditions, that comprise pharmaceutical lyacceptable charged vehicles, including but not limi ted tocationic surfactants, cyclodextrins, nanoparticles and microspheres,emulsionsorliposomes,with control the sizedistribution, potential, osmolality and pH. In a fu rtherembodiment of the invention, the intraocular compos itionproposed furthercomprises one ormore synergistic agents,including but not limited to neuropeptides, exosome s,mitochondrial-derived peptides, complement inhibito rs,senolytics, autophagy enhancers, antioxidants, saff ron, andnon-steroidal anti-inflammatory pharmaceutical drug s withpharmaceuticallyacceptable charged vehicle. The cannabinoid-based compositions provides neuroprotection,anti-inflammatory and antioxidant effectsthrough the activation of ECS, along with other int endedeffects on for ophthalmologic conditions, including but notlimited to neuroretinal dysfunction and retinal neurotoxicity.The invention aims to maximise neuroprotective effi cacywhile using the positive side effects that can be f ound andminimising the systemic side effects of other curre nt healthcare approaches. In this regard, the most general e mbodimentof the invention comprises a THC-based formulation for neuroprotection in ophthalmicconditions. Alternatively, the THC-based formulation furthercomprises CBD molecules. Said CBD molecules are ada pted toturn purple due to the increase in the concentratio n of thephotochemically unstable oxidation product HU-331.Advantageously, the dosing of the formulation to beconsideredcanbeestimated bycontrollingtheamo unt / volumedelivered, i.e., the increase in colouring is relat ed withthe increase in cannabinoid-based formulation deliv ered,which could enhance therapeutic efficacy and ensure patientsafety. It is also worth noting that CBD has analge sic andantioxidant properties, along with the neuroprotect iveantioxidant and anti-inflammatory effect of THC in the contextofretinalneurotoxicity. The formulation can optionally further comprise thecombination of other compounds for ophthalmic preve ntion andmanagement of neuroretinal dysfunction, included bu t notlimited to Neuropeptides, Exosomes, Mitochondrial-d erivedPeptides, Complement Inhibitors, Senolytics, Autoph agyEnhancers, Antioxidants, Non-steroidal Anti-inflamm atoryPharmaceuticalDrugs,and the components presented in the listbelow: The main embodiment of the invention also comprises theiontophoretic delivery of the said THC-based formul ation.Advantageously, the iontophoretic delivery reduces thedelivery loss to targeted tissues by limiting absor ptionrisks by intermediates and by improving the guidanc e ofionized molecules. Preferably, the iontophoretic formulation deliverymethod is adapted to target the retinal barrier and retinaloptical nerve, although it can be adapted to otherintraocular tissues considering that the pharmaceut icalcompound must traverse various multi-layered barrie rs, suchas the eyelid for assistance and prevention of symp tomsassociated with the periocular skin and eyelidconditions / procedures needed in a healthcare settin g or thecorneal protection due to the small retention of th ecannabinoid-molecules within the innerlayermembra nes giventhe presence of ECS in the biomolecular membranes a ndstructuresofthe human eye. The usage of THC-based molecules combined with CBD- basedmoleculesbring additional anti-inflammatory andan tioxidantproperties along with photoprotective properties an dneuroprotective effect.The iontophoretic delivery of saidformulation to the posterior segment of the eye slo ws theprogression ofvision loss. FIGURES Figure 1 shows a schematic representation of theintraocular delivery of cannabinoid-based compositi ons uponiontophoresis application into the posterior segmen t of theeye where the plus sign represent the charged molec ules, thearrows indicate the direction of their movement fol lowingthe application ofa low electriccurrent. DETAILED DESCRIPTION OF THE INVENTION The most generic and preferred embodiment of the pr esentinvention includes a method for the management of o phthalmicconditions and dermatological conditions, which com prisesthe use of cannabinoid-containing formulations, aninnovative technique for the intraocular iontophore ticdelivery for neuroprotection in ophthalmic conditio ns.The ECS is a complex and dynamic cell-signallingframework regulated bylipid-based endocannabinoids , suchas2-arachidonoyl glycerol (2-AG)andarachidonoyleth anolamide(anandamide or AEA). These endocannabinoids interac t with Gprotein-coupled cannabinoid receptors (CB1R and CB2 R) tofacilitate various physiological processes (Lu and Mackie,2016; Schwitzer et al., 2016). The CB1R are predominantly localised in the centralnervous system (CNS), specifically in the cortex, b asalganglia, hippocampus and cerebellum, where they out numbermanyotherreceptortypes.Incontrast,CB2Rarema inlyfoundin peripheral organs, particularly in immune tissue s. Theyplay a crucial role in regulating and maintaining i mmunefunction. Empirical studies have shown that they ca n helpregulate intestinal inflammation, contraction, and painassociated with inflammatory bowel conditions (Brad shaw andWalker, 2005; Lu and Mackie, 2016; Schwitzer et al., 2016). The endogenous or exogenous signals can trigger the ECSto act as a neuromodulatory system in the developme nt of theCNS. This influences neuronal synaptic plasticity a ndtransmission, as well as the regulation of various physiologicalfunctions,such asbodytemperature, movement and motor coordination, learning and memory, pain modulation, inflammatory and immune responses,cardiovascular function, sleep, and visual processi ng by theopticalnerve (Bradshaw and Walker, 2005; McCormick et al., 2019; Schwitzer et al., 2016). In addition to the endogenous activation of the cannabinoid system,exogenous cannabinoids such as THC and CBD presentin Cannabisinteracthighlywiththecannabinoidreceptors CB1R and CB2R (Saraiva et al., 2023). Thecannabinoid receptors are also the primary target o fexogenouscannabinoids. Cannabis is a plant that belongs to the family Cannabaceae and can be separated itinto three subspeciesdefined by their phytocannabinoid content. (Saraiva et al.,2023; Tahir et al., 2021). Cannabis sativa contains a widerange of bioactive compounds including phenols, fla vonoidsand anthraquinones. The THC and CBD are the most st udiedones, due to their biopharmaceutical properties and recentassociation with neuromodulatory systems when inter actingwith ECS leading to neuronal synaptic communication andaffect biological functions (Zantut et al., 2020).The interest in the pharmacological cannabinoids-ba sedmolecules is highly increasing in a wide range of m edicalresearch. Many studies demonstrated the effect ofcannabinoids on CNS and in the human ocular tissue, moreexactly in retina, playing a key role in visual inf ormationprocessing, along with the production of anti-infla mmatoryand neuroprotection effects in the brain (Aiello et al.,2020; Duraikkannu and Chatterjee, 2022; Fernández-Ruiz et al., 2013; Ibeas Bih et al., 2015; Nguyen and Wu, 2021; Tran etal.,2022). In particular, the presence of CB1 and CB2 receptor s wasinvestigated in the different layers of retina as w ell as inamacrine, RGCs, photoreceptors, rod bipolar, horizo ntal,retinal pigment epithelial cells (Borowska-Fielding et al.,2018; Bouskila et al., 2016; Duraikkannu and Chatterjee, 2022; Schwitzer et al., 2016; Zantut et al., 2020).Indeed,retinal function has been associated with modulatio n of theECS signalling pathway by being involved in the mod ulationof the release of neurotransmission signals within theretina, such as dopamine, noradrenaline, GABA and g lutamate,thatcontrolsynapticactivityinretinalganglion cellsandconsequentlymodulatevisualresponse (Bouskila et al., 2021;Zantutetal.,2020). Given the presence of cannabinoid receptors CB1R an dCB2R in the human CNS including the olfactory bulb,hippocampus, basal ganglia, and cerebellum, as well in thethalamus and cortex, known to influence visual outp ut, whichis reasonable to speculate that endogenous and exog enouscannabinoids have effects on the human brain and vi sion,meaning that ECS modulation on the retina might beparticularly relevant in potential management or pr eventionof retinal diseases, and neurological conditions in volvingthe retina by preventing neurodegeneration and reti nal cellsloss(Borowska- Fielding et al., 2018; Bouskila et al., 2021,2016; Zantut et al., 2020). Indeed, research conducted by Hampson A.J. et al.(Hampson et al., 1998) has established that THC and CBD, andseveral natural / synthetic cannabinoids are not onlyantioxidants as evidenced by cyclic voltammetry, bu t theyalso effectively prevent hydroperoxide-induced oxid ativedamage in both chemical (Fenton reaction) systems a ndneuronal cultures. These findings suggest that cann abinoidswill be a promising biopharmaceutical agent for oxi dativeneurologicaldisorders. However, CBD has a low binding affinity for CB1 receptors, mainly interacting with CB2R, which arepredominantly found in peripheral tissues and the i mmunesystem contributing to anti-inflammatory andimmunomodulatoryprocess,butalsofoundintheret inalglia,more specifically in the Müller cells (Borowska-Fie lding etal., 2018; Bouskila et al., 2016).CBD has been shown tohave analgesic (Petersen et al., 2023), anticonvuls ant,muscle relaxant (Isenmann et al., 2021), neuroprote ctive(Fernández -Ruiz et al., 2013), antioxidant (Atalay et al.,2019), and anti-psychotic activity (Waldo Zuardi et al.,2012). Moreover, Borowska-Fielding J et al. (Borowska-Fieldinget al., 2018) demonstrated that cb2 deletion altered retinalvisual processing and the cannabinoid-related enzym aticprofile in murine models, since CBD modulates the E CS byinfluencing the activity of enzymes responsible forendocannabinoid breakdown, indirectly affecting can nabinoidreceptors and other non-cannabinoid receptors (Borowska-Fielding et al., 2018; Bouskila et al., 2021; Watkins, 2019; Zantutetal.,2020). In particular, CB2 agonist treatment using cannabid iol,have shown potential in Alzheimer’s disease (AD) ma nagement.They regulate microglial activity, control cytokine release,and facilitate amyloid clearance, leading to the im provementof cognitive performance in AD models. Additionally , theyinhibit neuropathological progression related to mi croglia,astrocytes, and amyloid, further enhancing cognitiv eperformance. While the main focus will be the retinal barrier an dretinal optical nerve, it’s important to consider t hat thecannabinoid-based formulations must traverse variou s multi-layered barriers in the eye. As a result, there may be smallretention of the molecule within the inner layer me mbranesdue to the presence of ECS in the biomolecular memb ranes andstructures of the human eye. This can be consideredbeneficialasitwillprotectthecorneaandanteri orsegmentof the eye during the medical procedure and provide greatercomfort for the patient. Similar, the innovation de scribedcanbeapplicableasanocularroutetodeliveryca nnabinoid-based formulationsto the brain asa positive side effect. In parallel,the cannabinoid-based composition can alsobe formulated to be applied to the eyelid for the a id andprevention of symptoms of periocular skin and eyeli dsconditions / procedures along with corneal protection , ascannabinoid molecules present analgesic and antioxi dantproperties, along with the neuroprotective antioxid anteffectin contextofretinalneurotoxicity. Studies shown that although the expression of CBR i ncornea and retina occurs under healthy conditions, theoverexpressionofthisreceptorscanbemodulatedb yexternaland internal triggers such as environmental stress,infections and surgery (Aiello et al., 2020; Nguyen and Wu,2021; Tran et al., 2022).Upon induced cornealinjury,theECS is activated not only in the cornea but also in thebrain,inducinginfiltrationofimmunecellsintot heinjuredtissue and may also be involved in the regulation o f cellproliferation corn (Aiello etal.,2020). This invention contributes significantly to prevent ingand repairing neurodegeneration in neuroretinal dys functionand retinal neurotoxicity context, since said exoge nouscannabinoids present anti-inflammatory, antioxidant andphotoprotectiveproperties alongwithneuroprotecti veeffectby activating of the ECS present in the human eye a nd thebrain through a ocular route, leading to a more tar get-delivery of the purposed pharmaceutical composition in thebiomolecularmembranesand structures. As mentioned, the main embodiment of the invention describes an intraocular iontophoretic delivery of cannabinoid-based molecules for neuroprotection inophthalmic conditions. Ocular iontophoresis consist stypically of applying an electric field to active s ubstancesinordertoguidethem,onceionized,intodetermin atetargetocular tissues. Iontophoresis is a non-invasive tec hniquethatpromotes the diffusion ofbioactive molecules acrossfunctional barriers applying a small physical force of anelectricfieldtoenhancethediffusionofthephar maceuticalmolecules through eye barriers and membranes. Thosepharmaceutical compositions are used as neuroprotec tionagents due to their anti-inflammatory, antioxidant and photoprotective properties.Furthermore, the pharmaceutical compositions of sai dinvention can optionally comprise pharmaceuticallyacceptable charged vehicles, including but not limi ted tocationic surfactants, cyclodextrins, nanoparticles andmicrosphere, emulsions or liposomes, with control s izedistribution,potential,osmolalityand pH. The chemical structures of cannabinoid molecules po sechallenges fortheirdelivery to specific sections of theeye, since those are lipophilic compounds, which ma kesdifficult for them to be delivered to the aqueous h umour andvitreous humour of the eye, which are primarily com posed ofwater. The present method of the invention modifies thepharmaceutical formulation to make them more water- solublewhich improves their bioavailability and allows for theirdelivery to the posterior segment of the eye. In pa rallel,it will improve comfort, minimize visual blur oninstillation,increaseproductsolubility, increase moleculeresidence time and permeation through the cornea to achievegreater intraocular delivery, reducing systemic abs orption,and takes in advantage of the positive side effects on theanteriorsegmentofthe eye.Thus, the innovative approach presented offers a sa ferand more effective method for ocular surgeries, pot entiallyrevolutionizing the field of ophthalmologyand sign ificantlyimproving neuroretinal protection outcomes and pati entsafety. In an alternative embodiment of the present inventi on,the iontophoretic method is adapted to deliver saidformulationstotheeyelidsandsurroundingskin.T heeyelidsprovide coverage of the cornea and help in the dist ributionand clearance oftears.The delivery ofthe to the eyelids leadstotheassistanceandpreventionofsymptoms associatedwith the periocular skin or in eyelids procedures w here theprotection from surgical light or laser is needed.Furthermore, the CBD-based formulation presents ana lgesic,neuroprotective and antioxidant effects, as well asphototoxicity protection properties. This method ofapplication can also be used for long-term health c arealternative, in case the patient is not comfortable withother delivery options, such as to intravitreal inj ectionapproaches. The preferred pharmaceutical formulation to carry acharge, as iontophoresis operates by using an elect riccurrent to drive charged drug molecules through var iousmulti-layered barriers of the eye that prepared as a solution,suspension,dispersion,oremulsionisa THC-basedformulation comprising THC-based molecules and a chargedvehicle, either sterile water or an ionic buffer so lution aswell as nanoparticles, nanomicelles, nanoemulsion,microsphere, emulsions, cationic surfactants, cyclo dextrinsor liposomes carrier systems with control size dist ribution,potential,osmolality,and pH. Alternatively,the formulation furthercomprisesa CBD- based molecule. The application of alternative cannabinoid-basedformulations is useful for ocular administrationst rategies,creating a coloration trace on the sclera limbus an dcolorationintheposteriorsegmentoftheeye,dem onstratingthe transport of the emulsion to the retinal biolog icaltissues and membrane. Iontophoresis is also an effe ctivetechnique for intraocular delivery of cannabinoid-b asedcharged formulations isolated or with a pharmaceuti callyacceptable charged vehicle including but limited to thecarrier, diluent or excipient that must be compatib le withthe other ingredients of the formulation and safe t o thepatient, including but not limited to cationic surf actants,cyclodextrins, nanoparticles and microsphere, emuls ions orliposomes, with control size distribution, potentia l,osmolalityand pH. Alternatively, said formulation further contains on e ormore agents, including but not limited to neuropept ides,exosomes, mitochondrial-derived peptides, complemen tinhibitors, senolytics, autophagy enhancers, antiox idants,saffron, and non-steroidal anti-inflammatory pharma ceuticaldrugs with pharmaceutically acceptable charged vehi cle.The present invention relates to a pharmaceutical composition forassistance in retinaldegeneration thatwas developed and optimized foriontophoresis delivery to the retina, considering factors such as pharmaceuticalcomposition, stability and biocompatibility with oc ulartissues. The composition comprises a cannabinoid-ba sedcomposition isolated or conjugated with one or more agents.The unique combination of these agents, each with t heir ownproven neuroprotective, anti-inflammatory and antio xidantproperties, provides a synergistic effect that impr oves theoverall neuroprotective effect of the purposed inno vationcomposition. The amount of composite or bioactive a gentneeded varies depending on the desired biological e ndpoint,the specific agent, the encapsulating matrix compos ition,and the targettissue. Preferably, the concentration of THC in the formula tionis in between 0.001 and 20% and mostpreferably in between 0.01 and 5 %. Preferably, the concentration of CBD in the formula tionis in between 0.001 and 20% and mostpreferably in between 0.01 and 2 %. Preferably, the concentration of other synergisticagents in the formulation is in between 0.001 and 2 0% andmostpreferablyin between 0.01 and 5 %.The composition is designed for iontophoretic deliv eryto the eye. This invention further relates to an enhanced iontophoresis medicalmethod forimproved delivery ofsaidpharmaceutical compositions consisting of intraocul ariontophoreticdeliveryofcannabinoid-based formula tions,byensuring precise and controlled product delivery to theposterior segment of the eye through the passage of complexmembranes and structures of the eye, since CBD-cont ainingformulationscan create a violet / purple-coloration trace on the sclera limbus,colouring the posteriorsegment of theeye, demonstrating the transport of the emulsion to thetarget-retinal biological tissues and membrane in a controlprocedure enhancing therapeutic efficacy and ensuri ngpatientsafety. Non-invasive iontophoretic delivery enhances patien tcompliance, making it an ideal solution for long-te rmmanagement of chronic ocular or eyelids conditions, therebybypassing the need forinvasive proceduressuch as surgical implantation or high-dose intravitreal injections, alongwith minimization of additional ocular trauma. Furt hermore,it is a cost-effective alternative to surgical proc eduresand can be swiftly administered in a standard clini calsetting during a routine eye care appointment, excl uding theneed fora specialized surgicalenvironment. Preferably, the method is to be used in targeting t heretinal barrier and retinal optical nerve. Hence, i t’simportant to consider that the bioactive compound m usttraverse various multi-layered barriers which may p artlyretain of the molecule within the inner layer membr anes dueto the presence of ECS in the biomolecular membrane s andstructuresofthe human eye.Given thatECS can be found inthe cornea, new possibilities are arising for the p otentialpharmaceutical sideeffectofcannabinoid-basedfor mulationsdescribed above in a group of several conditions th ataffecting the cornea,along with protection ocular surface enhancementthrough the activation ofECS,as well as itcould potentially reestablish tear production homeo stasiswith the improve and restore the function of the co rnealepithelialbarrier. Evaluation of the pharmaceutical compound retentionwithin inner layer membranes and assessment of pote ntialinteractions with the ECS in the corneal epithelium isperformed along with the optimization of the pharma ceuticaldelivery strategies to maximize efficacy and safety .Advantageously, the pharmaceutical compositions can beprepared asa solution,suspension,dispersion,or emulsionusing established methods in the field. All procedu res arecarried out under the necessary conditions for theproduction, management, and processing of pharmaceu tical-grade materials. The mixture is then sterilized and packagedinto suitable containers for storage and transporta tion.The generic iontophoretic device comprises twocomponents: an ocular applicator and a return elect rode. Theocular applicator is designed to accommodate the de livery ofstabilizedaqueous-basedcannabinoidformulationsc omprisingthe following: a polycarbonate or polyvinylchloridereservoir and a stainless-steel electrode connected to thegenerator. The reservoir’s diameter and height shou ld bewithin a range suitable for ocular application, suc h as adiameter of 7-11 mm and a height of 3-6 mm, and the volumeshould be within a range that ensures effective del ivery ofthe formulations comprising between 0.3 and 0.7 ml, with anoptimum volume of0,5 ml. The intraocular iontophoretic method of delivery of aTHC-based formulation isolated or associated with C BD-basedmolecules or other agents for neuroprotection in op hthalmicconditionscomprisesthe following steps: -Ensuring the ocular applicator and return electrode areconnected to a powergenerator - Configuring the generator to operate at a constant currentwithin the range of0.025 mA to 25 mA -Applying the ocular applicator to the eye for a dur ationof0.05 minutesto 50 minutes - Disconnecting the device safely The manufacturing of cannabinoid-based pharmaceutic alformulations comprises several critical steps desig ned toensure the stability, efficacy, and safety of the f inalproduct. Initially, high-purity cannabinoid extract s,includingTHCisolatedorassociatedwithCBDandp otentiallyothercannabinoids,aredissolvedinalipidiccarr iersystemsuitable for ophthalmic use, such as MCT oil or 90 H phospholipid. The lipidic carriersystem enhances the solubility andfacilitate ocular absorption of poorly soluble acti vepharmaceutical ingredients within the tear fluid, t herebyincreasing their bioavailability. Factors such as v iscosityand particle size have a significant impact on ocul ar drugabsorption.Consequently,optimising these factors in theformulations using MCT or 90 H phospholipid can res ult inenhanced pharmaceutical outcomes. This could be for mulatedwith ionic conductivity without compromising the so lubilityoflipid-soluble cannabinoids. Each batch is subjected to a series of rigorous in-process quality testing, including pH balance, osmo larity,sterility, and particle size distribution. The main tenanceof the electrical properties of the formulation dur ingmanufacturing is a critical factor, therefore, elec trolytesolutions and buffers are used into the base soluti on toform a homogeneous iontophoretic medium. The pH of thepharmaceutical composition must be within the range of 6.5–7.8, so suitable buffers are used to control and ma intainthe pH during storage. The tonicity of the solution ,suspension, dispersion, or emulsion needs to be sim ilar tonatural tears (0.9% saline). Acceptable range is 0. 5–2%saline tonicity. Depending on the stability of the cannabinoid-basedmolecules,two possible methodsare asfollows: - Autoclaving: Sterilisation of the final high temperature stable product by autoclaving (saturate dsteam at121-132°C)for15 minutes. - Filter sterilisation: Sterilise the solution by filtrationthrougha0.22 μm filterintoasterilefinal containerunderasepticconditions. The final product is then filled into aseptically sterilised single-dose containers suitable forthe product and fitted with tamper-evidentseals.This process ensurespatient safety and product integrity during distrib ution andstorage. Quality control (QC) testing of cannabinoid-based e yedrops involves a series of rigorous tests to ensure productsafety, efficacy and consistency in accordance with medicaldevice quality requirements. The quality testing co mprises:-Conductivity monitoring by continuously ensuring optimal conductivity for effective pharmaceutical formulation deliveryvia iontophoresis. -Sterility Testing:Conducted underthe standards required to ensure no microbial contamination throughoutthe product'sshelflife. -pH ofthe ionic solution:Criticalforensuring the product's comfort and safety upon ocular application. The pH is maintained within a physiologically acceptable range (typically 6.5 to 7.5)underthe standardsrequired. -Cannabinoid Concentration and Stability Testing: Utilizing High-Performance Liquid Chromatography (HPLC)to verify the concentration ofcannabinoids and ensure their stability over time, under variousstorage conditions. -Particulate Matter Testing: Ensuring the solutionis free from particulate matter using light obscuration particle counttestin accordance with the standardsrequired. - Preservative Efficacy Test: Conducted as per standards required to confirm the effectiveness of the antimicrobial preservatives included in the formulation.The formulation of the cannabinoid-based formulatio ns isoptimised for iontophoretic delivery. This includesadjusting the pH to ensure thatthe drug isin its ionisedform and possibly using a hydrogel application or t hecannabinoid-based effect the adhesion-adhesion, sin ce THCand CBD provide adherence of the formulation to the cornealmembranes and tissues by interaction with ECS recep tors,which can reduce mechanical damage to the ocular su rfaceand increase the efficiency of iontophoresis.

Claims

CLAIMS1. TheuseofaTHC-containingsolutionforthemanufa ctureof ophthalmic formulations and products for the treatment of neuroretinal degeneration when administered to a human patient by means of iontophoresis.

2. A cannabinoid-based formulation for ocular allergy andinflammation in ophthalmic diseases treatment comprising the use THC-based molecules.

3. The cannabinoid-based formulation of Claim 1 furthe rcomprising the used ofCBD-based molecules.

4. The cannabinoid-based formulation of Claims 2 and 3further comprising one or more synergistic agents, including but not limited to non-steroidal anti- inflammatory and antihistamines pharmaceutical formulations.

5. A method to deliver the pharmaceutical formulationdescribedinclaims1to4throughmeansofionopho resiscomprising the steps: -Ensuring the ocular applicator and return electrodeare connected to a powergenerator - Configuring the generatorto operate ata constant currentwithin the range of0.025 mA to 25 mA - Applying the ocular applicator to the eye for a duration of0.05 minutesto 50 minutes - Disconnecting the device safely6. Amethodformanufacturingcannabinoid-basedophtha lmicsolutions, comprising:- Dissolving high-purity cannabinoid extracts, including THC and / or CBD, in a carrier suitable forophthalmicuse, - Optimizing the viscosity and particle size ofthe formulation to enhance iontophoretic delivery by 1sterilisation ofthe finalhigh temperature stable productby autoclaving atsaturated steam at121- 132°C for 15 minutes or by filtering through a 0.22μm filter into a sterile final container under asepticconditions. - Conducting quality control tests on the final product,including: o Ensuring optimal conductivity for effective pharmaceutical formulation delivery via iontophoresis o Ensuring no microbialcontamination throughout the product'sshelflife o Ensuring the productpH is maintained within a physiologically acceptable range,specifically between 6.5 and 7.5 o Verifying the concentration of cannabinoids using High-Performance Liquid Chromatography (HPLC) o Ensuring the solution is free from particulate matterusing lightobscuration particle count test 2

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