Pharmaceutical formulations comprising gabapentinoids for treating ocular neuropathic pain

Abstract

Disclosed herein are ophthalmic pharmaceutical compositions, eye drop formulations, nanoparticle formulations, and liposome formulations comprising gabapentinoids for treating ocular neuropathic pain.

Description

PHARMACEUTICAL FORMULATIONS COMPRISINGGABAPENTINOI DS FOR TREATING OCULAR NEUROPATHIC PAINCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 656,155 filed June 5, 2024. The content of the above-identified application is hereby incorporated herein by reference in its entirety.FIELD OF THE INVENTION

[0002] This disclosure provides ophthalmic pharmaceutical compositions, eye drop formulations, nanoparticle formulations, and liposome formulations comprising gabapentinoids for treating ocular neuropathic pain.BACKGROUND

[0003] Ocular neuropathic pain (e.g., corneal neuropathic pain) refers to discomfort or pain in the eye that arises from damage or dysfunction to the nerves responsible for transmitting sensory information. These nerves, particularly those in the cornea and surrounding areas, can become damaged due to various factors such as injury, infection, surgery, or underlying medical conditions like diabetes or herpes zoster.

[0004] The need for innovative treatments for ocular neuropathic pain stems from the shortcomings of existing medications, which frequently lead to unwanted side effects. Addressing this type of pain poses challenges for systemic pain medications due to the distinctive structure of corneal nerves. These medications must follow intricate pathways within the body to reach the cornea in effective amounts, often requiring higher doses that heighten the risk of adverse reactions. Furthermore, the increasing apprehension regarding opioid-based pain therapies and their addictive potential emphasizes the urgency for alternative treatment options.

[0005] Gabapentinoids, commonly used orally to manage neuropathic pain, fibromyalgia, and as an adjunct therapy for partial seizures, represent a significant advancement in pain management. Operating by binding to the alpha-2-delta subunit of voltage-gated calcium channels in neurons within the central nervous system, Gabapintinoids modulate pain transmission by reducing neurotransmitter release. However, systemic administration of gabapintinoids poses risks of systemic side effects, including dizziness, fatigue, andconfusion, which can significantly impact patients’ quality of life, particularly during prolonged therapy.SUMMARY

[0006] Disclosed herein are ophthalmic pharmaceutical compositions, eye drop formulations, nanoparticle formulations, and liposome formulations for treating ocular neuropathic pain. The presently disclosed ophthalmic pharmaceutical compositions and methods for treating ocular neuropathic pain offer enhanced and novel solutions for treating this condition.

[0007] Disclosed herein are ophthalmic pharmaceutical composition comprising a gabapintinoid, or a pharmaceutically acceptable salt thereof, one or more viscosity enhancers, one or more buffers, one or more preservatives, a pharmaceutically acceptable carrier, and optionally one or more antioxidants, wherein the ophthalmic pharmaceutical formulation composition has a pH of about pH 7.0 to about pH 7.4.

[0008] In embodiments, the ophthalmic pharmaceutical composition further comprises

[0009] In embodiments, the gabapintinoid is

[0010] In embodiments, the gabapintinoid is

[0011] In embodiments, the one or more viscosity enhancers is hydroxypropyl methylcellulose (HPMC) and / or polyvinyl alcohol (PVA).

[0012] In embodiments, the one or more buffers is borate buffers, phosphate buffers, citrate buffers, and acetate buffers.

[0013] In embodiments, the one or more preservatives are selected from polyquaternium-1, stabilized oxychloro complexes (SOC or Purite®), and sodium perborate.

[0014] In embodiments, the one or more antioxidants is sodium ascorbate and / or butylated hydroxytolune.

[0015] In embodiments, the ophthalmic pharmaceutical composition further comprises artificial tears, a corticosteroid, an anti-inflammatory agent, or any combination thereof.

[0016] In embodiments, the ophthalmic pharmaceutical composition comprises and antiinflammatory agent, wherein the anti-inflammatory agent is selected from lifitegrast, perfluorohexyloctane, bromfenac, nepafenac, ketorolac, diclofenac, suprofen, flubiprofen, and loteprednol.

[0017] In embodiments, the carrier is suitable for topical administration to the eye.

[0018] In embodiments, the carrier comprises a liposome.

[0019] In embodiments, the ophthalmic pharmaceutical composition is formulated as a cream, a foam, a paste, an ointment, an emulsion, a liquid solution, an eye drop, a gel, a spray, a suspension, a microemulsion, microspheres, microcapsules, nanospheres, nanoparticles, lipid vesicles, liposomes, polymeric vesicles, a patch, or a contact lens.

[0020] Also disclosed herein are an eye drop formulations comprising the ophthalmic pharmaceutical composition of the invention.

[0021] Nanoparticle formulations comprising the ophthalmic pharmaceutical composition of the invention are also disclosed. In embodiments, the nanoparticle formulation further comprises a surface modifying polymer. In embodiments, the surface modifying polymer is polyethylene glycol (PEG).

[0022] Liposome formulations comprising the ophthalmic pharmaceutical composition of the invention are also disclosed herein. In embodiments, the liposome comprises one or more phospholipid bilayers and an aqueous core. In embodiments, the liposome formulation is a controlled-release formulation.

[0023] In embodiments of the liposome formulations,is encapsulated in the aqueous core of the liposome.

[0024] In embodiments of the liposome formulations,is encapsulated in the aqueous core of the liposome.

[0025] In embodiments of the liposome formulations,is encapsulated in the phospholipid bilayer of the liposome.

[0026] Also disclosed herein are methods of treating ocular neuropathic pain, comprising ocularly administering the ophthalmic pharmaceutical compositions of the invention, the eye drop formulations of the invention, the nanoparticle formulation of the invention, or the liposome composition of the invention to a subject. In embodiments, the ocularneuropathic pain arises from dry eye, trauma, a corneal abrasion, a corneal burn, a corneal transplant, an autoimmune disease, an allergen, or surgery. In embodiments, ocularly administering the ophthalmic pharmaceutical composition reduces pain in one or both eyes of the subject.Also disclosed herein are methods of treating inflammation, comprising ocularly administering the ophthalmic pharmaceutical compositions of the invention, the eye drop formulations of the invention, the nanoparticle formulation of the invention, or the liposome composition of the invention to a subject. In embodiments, the subject has an eye disease that causes ocular inflammation (e.g., uveitis, uveoretinitis, or proliferative vitreoretinopathy). In embodiments, the eye disease causes extraocular inflammation (e.g., corneal inflammation, neuropathology, episcleritis, or scleritis). In embodiments, the method comprises ocularly administering the ophthalmic pharmaceutical composition reduces inflammation in one or both eyes of the subject.DETAILED DESCRIPTION

[0027] Gabapintinoids, typically administered orally for treating neuropathic pain, fibromyalgia, and as an adjunct therapy for partial seizures, signify a notable advancement in pain management. Their mechanism involves binding to the alpha-2-delta subunit of voltage-gated calcium channels in neurons of the central nervous system, thereby regulating pain transmission by decreasing neurotransmitter release. Although effective when taken systemically, this mode of delivery poses the risk of systemic side effects such as dizziness, fatigue, and confusion, which can considerably affect patients’ quality of life, especially during prolonged treatment regimens.

[0028] Disclosed herein are ophthalmic pharmaceutical compositions containing gabapintinoids, along with methods for treating in ocular neuropathic pain therewith. This approach targets the medication directly to the site of pain — the cornea, known for its dense sensory innervation and unique physiological traits. By concentrating the treatment locally, the ophthalmic composition reduces systemic absorption, potentially decreasing the systemic side effects often linked with oral or systemic administration. This localized strategy enables a higher concentration of the drug to be delivered precisely to the affected area, enhancing effectiveness while limiting drug exposure to the rest of the body.

[0029] Targeted delivery of the ophthalmic pharmaceutical compositions of the invention is particularly advantageous for managing corneal neuropathic pain. Systemic medications must undergo a complicated pharmacokinetic process to attain effective concentrations in the cornea, often necessitating higher doses that heighten the risk of adverse effects. The eye drop formulation overcomes these obstacles by providing a direct method of delivery, ensuring that more medication reaches the affected area with fewer systemic consequences.Definitions

[0030] Before describing the present disclosure in detail, it is to be understood that this present disclosure is not limited to particular compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0031] As used herein, the singular forms “a,” “an,” and “the” include both singular and plural references unless the context clearly indicates otherwise. Thus, for example, reference to “a molecule” optionally includes a combination of two or more such molecules, and the like.

[0032] As used herein, the term “about” refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.

[0033] As used herein, the term “and / or,” as in a phrase such as “A and / or B,” is intended to include both A and B; A or B; A (alone); and B (alone). Likewise, as used herein, the term “and / or,” as in a phrase such as “A, B, and / or C,” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0034] As used herein, the terms “individual,” “patient,” or “subject” refer to a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice, hamsters, and rats). In embodiments, the individual, patient, or subject is a human.

[0035] As used herein, the term “treatment” refers to clinical intervention designed to alter the natural course of the individual or cell being treated during the course of clinical pathology.Desirable effects of treatment include, for example, decreasing the rate of disease progression, ameliorating or palliating the disease state, and improved prognosis. An individual is successfully “treated,” for example, if one or more signs or symptoms associated with the disorder are mitigated or eliminated. For example, an individual is successfully “treated” if one or more symptoms associated with ocular neuropathic pain are mitigated or eliminated, including, but are not limited to, decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, and / or delaying the progression of the disease.

[0036] An “effective amount” refers to at least an amount effective, at dosages and for periods of time necessary, to achieve the desired or indicated effect, including a therapeutic result. An effective amount can be provided in one or more administrations.

[0037] The term “gabapentinoid” refers to a class of drugs that are derivatives of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA; z.e., GABA analogues), which block 0128 subunit-containing voltage-dependent calcium channels (VDCCs). This site has been referred to as the gabapentin receptor (0126 subunit), as it is the target of the drugs gabapentin and pregabalin.

[0038] Clinically used gabapentinoids include gabapentin, pregabalin, and mirogabalin, as well as a gabapentin prodrug, gabapentin enacarbil, the chemical structures of which are shown below.mirogabalin gabapentin enacarbilAdditionally, phenibut has been found to act as a gabapentinoid in addition to its action of functioning as a GAB AB receptor agonist. The chemical structure of phenibut isphenibut

[0039] Gabapentin, 2-[l-(Aminomethyl)cyclohexyl]acetic acid, sold under the brand names Neurontin® (Pfizer), Gralise® (Alamica), Horizant® (Arbor), and Neuraptine® (Nubratori)), has the chemical structure:Formulations of gabapentin have been disclosed in, inter alia, U.S. Patent Nos. 6, 054,482; 7,256,216; 6,340,475; 6,635,280; 6,488,962; 6,723,340; 7,438,927; 8,192,756; 8,252,332; 8,333,992; and 7,731,989.

[0040] (5)-3-isobutyl-y-aminobutyric acid (also referred to as “pregabalin” and sold under the brand name Lyrica® (Pfizer)) has the chemical structure:Formulations of pregabalin have been disclosed in, inter alia, U.S. Patent Nos. 8,945,620; 9,144,559; and 10,022,447.Compositions of the Invention

[0041] Disclosed herein are compositions containing a gabapintinoid, which are suitably formulated into ocular pharmaceutical compositions for ocular administration to subjects in a biologically compatible form suitable for ocular administration to an eye.

[0042] For example, solubility profile, partition coefficient, pH rate profile, pKa, stability in pharmaceutical solvents, drug-excipient interaction and effect of moisture, temperature, light, and oxygen on the gabapintinoid may be determined. Optionally, all excipients used in the formulation should be “Generally Regarded as Safe” (GRAS) and approved by Food and Drug Administration (FDA) and Health Canada for ocular delivery. Biopharmaceutical characterization, analytical methods development, optimization, and validation may be determined.

[0043] In embodiments of the ophthalmic pharmaceutical composition, the gabapintinoid is pregabalin.

[0044] In embodiments of the ophthalmic pharmaceutical composition, the gabapintinoid is gabapentin.

[0045] In embodiments of the ophthalmic pharmaceutical composition, the gabapintinoid is mirogabalin.

[0046] In embodiments of the ophthalmic pharmaceutical composition, the gabapintinoid is gabapentin enacarbil.

[0047] In embodiments of the ophthalmic pharmaceutical composition, the gabapintinoid is phenibut.Cyclosporine

[0048] Cyclosporine is a calcineurin inhibitor, having the chemical structure:

[0049] Cyclosporine is an immunosuppressant and works by blocking T-cell activation and interleukin-2 production. In ophthalmic formulations, it is frequently employed to treat chronic dry eye by lessening eye inflammation and boosting tear production. Its antiinflammatory properties complement the pain management of gabapentinoids, addressing the underlying inflammation often associated with neuropathic conditions in the cornea. This combination may improve overall treatment effectiveness, providing both antiinflammatory and pain-relieving effects, thereby reducing corneal inflammation associated with neuropathic pain.

[0050] Accordingly, in embodiments, the ophthalmic pharmaceutical composition further comprises cyclosporine.pH

[0051] Gabapentinoids necessitate a pH adjustment close to that of natural tears (usually around 7.0 to 7.4) to minimize ocular irritation and improve patient tolerance. Cyclosporine, on the other hand, remains stable within a slightly acidic to neutral pH range. The ideal pH for cyclosporine formulations typically falls between 6.5 and 8.0, with a preference towards the lower end of this spectrum to enhance solubility and prevent degradation. Achieving a pH that accommodates both cyclosporine and gabapentinoid stability is paramount. A pH range of approximately 7.0 to 7.4, closely mirroring the pH of natural tears, is likely to maintain the stability and efficacy of both cyclosporine and gabapentinoid while ensuring patient comfort. Accordingly, in embodiments, the ophthalmic pharmaceutical formulation composition has a pH of about pH 7.0 to about pH 7.4.Viscosity

[0052] Enhancing the viscosity of the ophthalmic pharmaceutical composition prolongs the drug's presence on the corneal surface, thereby improving drug absorption and effectiveness. Nevertheless, excessively high viscosity may result in blurred vision and discomfort.

[0053] Exemplary viscosity enhancers include, but are not limited to, hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), and polyvinyl alcohol (PVA). These viscosity enhancers are frequently employed in ophthalmic solutions to boost viscosity. They are generally well-tolerated and efficient in establishing a more stable tear film without substantially altering pH.Buffers

[0054] The buffer system must be carefully selected to keep the pH in the right range and avoid any negative interactions with the cyclosporine and / or gabapentinoid.

[0055] It is important for the buffer capacity to be strong enough to prevent pH changes from dilution or contact with tear fluid. This is especially crucial in formulations with two active pharmaceutical ingredients (APIs), as the interaction between the APIs and the buffer could potentially shift the pH outside of the desired range.

[0056] Exemplary buffers include, but are not limited to, borate buffers, phosphate buffers, citrate buffers, and acetate buffers, as well as other pharmaceutically acceptable buffers.Preservatives

[0057] Preservatives play a vital role in multi-dose eye drop formulations to prevent microbial growth. Nonetheless, many commonly used preservatives have the potential to cause ocular irritation or damage when used over a long period. Common options like benzalkonium chloride (BAK) are frequently used but can be irritating. Alternatives like polyquatemium- 1, stabilized oxy chloro complexes (SOC or Purite®), or sodium perborate may provide comparable antimicrobial effectiveness with lower toxicity.

[0058] Accordingly, exemplary preservatives include, but are not limited to, polyquatemium- 1, stabilized oxy chloro complexes (SOC or Purite®), and sodium perborate.Antioxidants

[0059] Antioxidants can be included to safeguard sensitive ingredients from oxidative breakdown, ensuring the stability and effectiveness of the composition.

[0060] Exemplary antioxidants include, but are not limited to, sodium ascorbate and / or butylated hydroxytolune.Additional Components

[0061] The ophthalmic pharmaceutical compositions of invention may include various additional components, including, but not limited to, artificial tears, corticosteroids, antiinflammatory agents, and combinations thereof.

[0062] In embodiments, the ophthamic pharmaceutical compositions of the invention comprise one or more anti-inflammatory agents. Exemplary anti-inflammatory agents include, but are not limited to, lifitegrast (Xilidra®), perfluorohexyloctane (Miebo®), bromfenac (Prolensa®, BromSite®, Xibrom®, Bromday®), nepafenac (Nevanac®), ketorolac (Acuvail®, Acular®, AcularLS®, Acular PF®), diclofenac (Voltaren Ophthalmic®), suprofen (Profenal®), flubiprofen (Ocufen®), and loteprednol (Lotemax®, Lotemax SM®, Alrex®, Eysuvis®).Pharmaceutical Formulations

[0063] The ophthalmic pharmaceutical compositions and methods of the present invention may be utilized to treat a subject with an ophthalmic condition such as ocular neuropathic pain. In embodiments, the subject is a human or a non-human mammal. When administered to an animal, such as a human, the ophthalmic pharmaceutical comprises a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well knownin the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In embodiments, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (z.e., routes, such as injection, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. In embodiments, the ophthalmic pharmaceutical composition is present in a solution suitable for topical administration, such as an eye drop.

[0064] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0065] A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition.

[0066] In embodiments, the carrier is suitable for topical administration to the eye.

[0067] The ophthalmic pharmaceutical composition is a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer. The pharmaceutical composition also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomal encapsulation of the ophthalmic pharmaceutical compositions of the invention can, for example enhance bioavailability and ocular efficacy compared to systemic drug injection. Liposomal formulations are established, safe and efficacious drug carriers for the delivery of poorly soluble lipophilicdrugs (Agarwal et al. Drug Delivery, 23(4), 1075-1091). Accordingly, in an embodiment, the carrier suitable for ocular administration to an eye comprises a liposome.

[0068] In embodiments, the liposome comprises one or more phospholipid bilayers and an aqueous core. As such, the liposome can encapsulate the gabapintinoid (e.g., pregabalin, gabapentin) in the aqueous core of the liposome and the cyclosporine in the phospholipid bilayer.

[0069] In embodiments, liposomal encapsulation provides a controlled release of the ophthalmic pharmaceutical composition of the invention.

[0070] The phrase “pharmaceutically acceptable carrier” as used herein may encompass a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) glycols, such as propylene glycol; (2) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (3) esters, such as ethyl oleate and ethyl laurate; (4) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (5) pyrogen-free water; (6) isotonic saline; (7) Ringer’s solution; (8) ethyl alcohol; (9) phosphate buffer solutions; and (10) other non-toxic compatible substances employed in pharmaceutical formulations.

[0071] An ophthalmic pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, as a cream, a foam, a paste, an ointment, an emulsion, a liquid solution, an eye drop, a gel, a spray, a suspension, a microemulsion, microspheres, microcapsules, nanospheres, nanoparticles, lipid vesicles, liposomes, polymeric vesicles, a patch, or a contact lens.

[0072] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both.

[0073] Dosage forms for topical administration include ophthalmic formulations, such as eye drops. The active compound may be mixed under sterile conditions with apharmaceutically acceptable carrier, and with any preservatives or buffers that may be required.

[0074] For use in the methods of this invention, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (e.g., 0.5 to 90%) of active ingredient(s) in combination with a pharmaceutically acceptable carrier.

[0075] Actual dosage levels of the active ingredient(s) in the pharmaceutical compositions may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0076] The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health, and prior medical history of the subject being treated, and like factors well known in the medical arts.

[0077] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By “therapeutically effective amount” is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient’s condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher el al. (1996) Harrison s’ Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).

[0078] In general, a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0079] If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In embodiments of the present invention, the active compound may be administered two or three times daily. In embodiments, the active compound will be administered once daily.Nanoparticle Formulations

[0080] Nanotechnology-based ocular drug delivery platforms could increase drug bioavailability to the eye. Since a nanoparticle formulation will tend to accumulate in the conjunctival cul-de-sac, the contact time of the nanoparticle drug formulation is considerably longer than comparable ophthalmic solutions. This increased contact time may give a longer duration of action.

[0081] In some embodiments, the gabapentinoid is adsorbed onto or entrapped within nanoparticles. The term “nanoparticle” encompasses particles, nanospheres, nanocapsules, liposomes, polymeric micelles, quantum dots, dendrimers, solid lipid nanoparticles, etc. Examples of nanoparticle formulations that could be used for ocular drug delivery are described in Deepak Thassu & Gerald Chader (eds.), Ocular Drug Delivery Systems: Barriers and Application of Nanoparticulate Systems (2013) CRC Press and Kewal K. Jai n, “Nanocarriers for Ocular Drug Delivery” in The Handbook of Nanomedicine (2008) Humana Press.

[0082] The nanoparticles may be made of any suitable material, including biocompatible polymers or biologic materials. Examples of such materials include chitosan, a polycarboxylic acid such as polyacrylic acid, hyaluronic acid esters, polyitaconic acid, poly(butyl)cyanoacrylate, poly-s-caprolactone, poly(isobutyl)caprolactone, poly(lactic / glycolic) acid, or poly(lactic acid), poly(ethylene glycol)-block-poly(L-lysine), EUDRAGIT® RS 100, or EUDRAGIT® RL100. The EUDRAGIT® materials are copolymers of ethyl acrylate, methyl methacrylate, and a low content of methacrylic acid ester with quaternary ammonium groups.

[0083] In some embodiments, the nanoparticles comprise polymers that are both biocompatible and biodegradable, such as polylactic acid, polyglycolic acid, poly(lactic / glycolic) acid, poly(caprolactone), polyhydroxobutyrate, chitosan, hyaluronic acid, poly(2-hydroxyethyl-methacrylate), and polyethylene glycol). In some cases, the nanoparticles comprise synthetically-made polymers that are both biocompatible and biodegradable.

[0084] In embodiments, the nanoparticles comprise a surface modifying polymer. In embodiments, the surface modifying polymer is polyethylene glycol (PEG).

[0085] The nanoparticles may have any suitable size less than 1 pm. In some embodiments, the nanoparticles have an average size diameter in the range of 100-700 nm. The resulting nanoparticle formulation may be in any suitable liquid form, including suspension, emulsion, gel, sol, liquid foam, etc.Methods and Uses

[0086] Without being bound by theory, the mechanism of action of gabapintinoids centers around their interaction with the alpha-2-delta subunit of voltage-gated calcium channels found on nerve cells. This binding is crucial for their role in modulating pain transmission, especially in treating neuropathic pain. The alpha-2-delta subunit is a regulatory component of voltage-gated calcium channels, which play a vital role in synaptic transmission. When gabapintinoids bind to this subunit, it reduces the influx of calcium ions into nerve terminals. This reduction in calcium entry results in a decrease in the release of various neurotransmitters, including glutamate, norepinephrine, and substance P, all of which are involved in pain signaling.

[0087] In the context of corneal nerves, this mechanism has unique implications. The cornea, densely innervated tissue in the human body, is primarily supplied by sensory nerves originating from the trigeminal ganglion. These nerves are critical for pain, touch, and temperature sensation. They are characterized by the presence of numerous voltage-gated calcium channels, including those containing the alpha-2-delta subunit targeted by gabapentinoids.

[0088] The direct application of gabapentinoids to the cornea via ophthalmic pharmaceutical compositions of the invention enables the drug to act locally at the nerve endings. This localized application ensures that gabapentinoids reach the corneal nerves in sufficient concentrations to effectively bind to the alpha-2-delta subunits. By modulating the activityof these calcium channels at the source of pain transmission, gabapentinoids provides relief from pain with a distinct advantage over systemic applications. Systemic administration of gabapentinoids must traverse through metabolic and circulatory systems before reaching peripheral target sites like the cornea, often with reduced efficacy and increased risk of systemic side effects.

[0089] The localized effect of gabapentinoids on corneal nerves allows for fast-acting relief by reducing the excitability of nerve fibers in the cornea, thereby diminishing abnormal pain signaling associated with corneal neuropathic conditions. This targeted action not only enhances treatment efficacy but also significantly reduces the likelihood of systemic side effects such as sedation or dizziness, commonly observed with oral or systemic gabapentinoids administration.

[0090] Accordingly, the present disclosure includes a method of treating ocular neuropathic pain, comprising administering ocularly to a subject the ophthalmic pharmaceutical compositions of the invention.

[0091] Most frequently described ocular neuropathic pain conditions are associated with corneal injury and inflammation; inflammation is a significant contributor to neuropathic pain syndromes (Guindon and Hohmann, Br J Pharmacol. 2008 Jan;153(2):319-34). Corneal neuropathic pain typically presents with allodynia (abnormal response to normal stimuli) and hyperalgesia (exaggerated response to mild noxious stimuli). Corneal pain conditions are very common as the cornea is highly innervated with sensory nerves. Accordingly, in an embodiment, the method is a method for treating ocular inflammation and / or neuropathic pain caused by a non-infectious condition. In embodiments, the ocular neuropathic pain is corneal neuropathic pain. In embodiments, the ocular neuropathic pain arises from dry eye, trauma (e.g., refractive surgery), a corneal abrasion, a corneal bum, a comeal transplant, an autoimmune disease, an allergen, or surgery.

[0092] In embodiments, the inflammation is caused by a subject having an eye disease (e.g., uveitis, uveoretinitis, or proliferative vitreoretinopathy). In embodiments, the eye disease causes extraocular inflammation (e.g., corneal inflammation, neuropathology, episcleritis, or scleritis).

[0093] In embodiments, the inflammation causes pain.

[0094] In embodiments, the method reduces pain in one or both eyes of the subject.Kits

[0095] Pharmaceutical kits comprising the ophthalmic pharmaceutical compositions as described above and a container holding the composition are also disclosed herein. The container contains the composition and has a dispensing means such as a dropping device adapted for topically administering the composition to the eye of a subject.

[0096] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0097] All publications, patents, patent applications, and / or other documents cited in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, and / or other document were individually and separately indicated to be incorporated by reference for all purposes.

Claims

CLAIMSWhat is claimed is:

1. An ophthalmic pharmaceutical composition comprising a gabapintinoid, or a pharmaceutically acceptable salt thereof, one or more viscosity enhancers, one or more buffers, one or more preservatives, a pharmaceutically acceptable carrier, and optionally one or more antioxidants, wherein the ophthalmic pharmaceutical formulation composition has a pH of about pH 7.0 to about pH 7.4.

2. The ophthalmic pharmaceutical composition of claim 1, further comprising3. The ophthalmic pharmaceutical composition of claim 1 or 2, wherein the gabapintinoid is4. The ophthalmic pharmaceutical composition of claim 1 or 2, wherein the gabapintinoid is5. The ophthalmic pharmaceutical composition of any one of claims 1-4, wherein the one or more viscosity enhancers is hydroxypropyl methylcellulose (HPMC) and / or polyvinyl alcohol (PVA).

6. The ophthalmic pharmaceutical composition of any one of claims 1-5, wherein the one or more buffers is borate buffers, phosphate buffers, citrate buffers, and acetate buffers.

7. The ophthalmic pharmaceutical composition of any one of claims 1-6, wherein the one or more preservatives are selected from polyquaternium-1, stabilized oxy chloro complexes (SOC or Purite®), and sodium perborate.

8. The ophthalmic pharmaceutical composition of any one of claims 1-7, wherein the one or more antioxidants is sodium ascorbate and / or butylated hydroxytolune.

9. The ophthalmic pharmaceutical composition of any one of claims 1-8, further comprising artificial tears, a corticosteroid, an anti-inflammatory agent, or any combination thereof.

10. The ophthalmic pharmaceutical composition of claim 9, wherein the anti-inflammatory agent is selected from lifitegrast, perfluorohexyloctane, bromfenac, nepafenac, ketorolac, diclofenac, suprofen, flubiprofen, and loteprednol.

11. The ophthalmic pharmaceutical composition of any one of claims 1-9, wherein the carrier is suitable for topical administration to the eye.

12. The ophthalmic pharmaceutical composition of any one of claims 1-9, wherein the carrier comprises a liposome.

13. The ophthalmic pharmaceutical composition of any one of claims 1-9, wherein the ophthalmic pharmaceutical composition is formulated as a cream, a foam, a paste, an ointment, an emulsion, a liquid solution, an eye drop, a gel, a spray, a suspension, a microemulsion, microspheres, microcapsules, nanospheres, nanoparticles, lipid vesicles, liposomes, polymeric vesicles, a patch, or a contact lens.

14. An eye drop formulation comprising the ophthalmic pharmaceutical composition of any one of claims 1-13.

15. A nanoparticle formulation comprising the ophthalmic pharmaceutical composition of any one of claims 1-13.

16. The nanoparticle formulation of claim 15, further comprising a surface modifying polymer.

17. The nanoparticle formulation of claim 16, wherein the surface modifying polymer is polyethylene glycol (PEG).

18. A liposome formulation comprising the ophthalmic pharmaceutical composition of any one of claims 1-13, wherein the liposome comprises one or more phospholipid bilayers and an aqueous core.

19. The liposome formulation of claim 18, wherein the liposome formulation is a controlled-release formulation.

20. The liposome formulation of claims 18 or 19, whereinis encapsulated in the aqueous core of the liposome.

21. The liposome formulation of claims 18 or 19,is encapsulated in the aqueous core of the liposome.

22. The liposome formulation of any one of claims 18-21, whereinis encapsulated in the phospholipid bilayer of the liposome.

23. A method of treating ocular neuropathic pain, comprising ocularly administering the ophthalmic pharmaceutical composition of any one of claims 1-13, the eye drop formulation of claim 14, the nanoparticle formulation of any one of claims 15-17, or the liposome composition of any one of claims 18-22 to a subject.

24. The method of claim 23, wherein the ocular neuropathic pain arises from dry eye, trauma, a corneal abrasion, a corneal bum, a corneal transplant, an autoimmune disease, an allergen, or surgery.

25. The method of claim 23 or 24, wherein ocularly administering the ophthalmic pharmaceutical composition reduces pain in one or both eyes of the subject.

26. A method of treating inflammation, comprising ocularly administering the ophthalmic pharmaceutical composition of any one of claims 1-13, the eye drop formulation of claim 14, the nanoparticle formulation of any one of claims 15-17, or the liposome composition of any one of claims 18-22 to a subject.

27. The method of claim 26, wherein the subject has an eye disease that causes ocular inflammation.

28. The method of claim 27, wherein the eye disease is uveitis, uveoretinitis, or proliferative vitreoretinopathy.

29. The method of claim 27 or 28, wherein the eye disease causes extraocular inflammation.

30. The method of claim 29, wherein the extraocular inflammation is corneal inflammation, neuropathology, episcleritis, or scleritis.

31. The method of any one of claims 26-31, wherein ocularly administering the ophthalmic pharmaceutical composition reduces inflammation in one or both eyes of the subject.

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