Surface ocular application of ambosol for ocular pain

Abstract

Methods and formulations for treating ocular pain, including nociceptive ocular pain and neurological ocular pain, are disclosed. The formulations include ambroxol or chemical derivatives thereof. The methods and formulations selectively inhibit Nav1.8 nociceptors, which allow for sensations while relieving pain. The formulations and methods provide effective and safer control of surface ocular pain compared to existing surface analgesic formulations and methods.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Application No. 63 / 344,561, filed May 21, 2022, the contents of which are incorporated herein by reference in their entirety.

[0003] background

[0004] The sensory systems of touch and pain provide us with information about our environment and our bodies that is often critical for survival and health. The sensation of this information about our environment and our bodies is encoded in the periphery and interpreted by the brain as touch and pain sensations. When functioning well, these circuits promote survival and prepare us to make adaptive decisions. Pathological loss of touch can lead to a perceived disconnection from the body, and insensitivity to pain can be dangerous, leading to maladaptive risky behaviors. Pain from tissue inflammation or injury can adversely affect the patient's quality of life, although in these cases, pain sensation acts as a protective mechanism for our body. On the other hand, conditions in which these systems begin to send pain signals in response to harmless touch or even in the absence of any observable sensory stimulation also have a huge negative impact on the patient's life.

[0005] The pain system of our ocular surface (essentially composed of the cornea and conjunctiva) is unique in its primary role of protecting, maintaining and restoring the optical tear layer, without which our vision would not be able to function. To meet this survival need, the neuronal network of the cornea has evolved into the most powerful, sensitive and complex pain system in the body, combined with sensors that are very susceptible to exposure to harmful environments. The cornea has the highest density of nociceptors of any tissue in the body and maintains an elevated level of sensitivity even to normal environmental stimuli. Therefore, eye pain mainly originates from ocular surface tissues, mainly from the cornea. Therefore, experiments on eye pain have focused on the ocular surface, mainly on the cornea. Due to the unique, highly functionally sensitive and structurally complex neurosensory system at the cornea, pain drugs that are effective in other parts of the body may not be effective or safe when used for ocular pain control.

[0006] For example, topical 0.1% diclofenac, a nonsteroidal anti-inflammatory drug (NSAID), does not have a clinically significant corneal anesthetic effect in humans. Commonly used topical ophthalmic anesthetics include, but are not limited to, tetracaine, proparacaine, lidocaine, and bupivacaine. Continuous topical application of anesthetics or NSAIDs to the eye is known to increase the incidence of infection and corneal scarring and delay corneal wound healing in patients with epithelial defects; long-term use increases the risk of corneal melting and even perforation. New pain management strategies with fewer side effects are needed to relieve ocular pain.

[0007] On the other hand, compared with physiological noxious eye pain, neuropathic ocular pain (NOP) is a series of ocular pain disorders caused by damage or disease affecting neural tissue, but the condition may also be caused by peripheral or central sensitization. NOP is common in diseases related to ocular surface tissue damage, such as infection, trauma, various ophthalmic surgeries (including laser refractive surgery) and chronic severe ocular surface damage (such as limbal stem cell deficiency and sequelae of chemical burns, etc.). When caused by peripheral or central sensitization, NOP patients may have little or no signs of ocular surface tissue damage and usually respond poorly to conventional analgesic treatments. These patients may also have pain symptoms that are disproportionate to the manifestations of their clinical disease.

[0008] The experience of pain sensation in NOP can vary widely, reflecting various causal factors, such as: the type of noxious stimulus that damages the ocular surface nociceptors, the type of corneal sensory receptors affected, the extent of the inflammatory response, and the type of disorders and injuries affecting the nervous system. Symptoms of NOP can range from devastating, unremitting eye pain and severe sensitivity to light (photophobia) in the worst cases, to mild hyperalgesia (increased sensitivity to sensory pain and extreme reactions to pain) or dysesthesia (distorted sensations, especially of touch).

[0009] The perception of distortion and pain levels can vary depending on the source of the maladaptive signal (e.g., abnormal axonal regeneration or peripheral sensitization). One or both eyes may be affected with varying severity. NOP is typically described as being localized in and around the eyes but can progress to peripheral areas of the face and head. Many comorbid conditions may predispose patients to NOP, including peripheral neuropathic pain, fibromyalgia, and Sjögren's syndrome. Improved treatments for ocular pain are needed, including reduction or elimination of nociceptive ocular pain and NOP.

[0010] Overview

[0011] The present disclosure provides a safer and more effective method and preparation for treating ocular pain in a subject, including noxious ocular pain and NOP. The present disclosure provides a method and preparation for alleviating or eliminating ocular pain in a subject, including noxious ocular pain and NOP. In various aspects, the use of a preparation for treating noxious ocular pain and / or NOP in a subject is disclosed. The treatment method includes the step of topically applying an effective amount of a preparation including a selective Nav1.8 inhibitor to the ocular surface of a subject suffering from noxious ocular pain and / or NOP. In some aspects, the Nav1.8 inhibitor is a peripheral nerve desensitizer. In some aspects, the Nav1.8 inhibitor comprises ambroxol and / or an ambroxol derivative.

[0012] In certain aspects, administration of the formulation provides partial preservation of sensation in the eye, including corneal sensation.

[0013] In certain aspects, the use or method further comprises administering an analgesic.

[0014] In various aspects, formulations comprising ambroxol and / or an ambroxol derivative and cyclodextrin are disclosed for use in treating nociceptive ocular pain and / or NOP in a subject.

[0015] In an embodiment, the formulation may include 0.01% to 10% by weight of ambroxol and / or an ambroxol derivative, based on the total weight or volume of the formulation.

[0016]

[0011] These and other features, aspects and advantages described herein will be better understood by those skilled in the art upon consideration of the following drawings, detailed description and appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The accompanying drawings, which are included and constitute a part of this specification, are included to illustrate certain aspects of the present invention. A clearer impression of the present invention and the components and system operations provided by the present invention will become more apparent by reference to the exemplary and therefore non-limiting embodiments shown in the drawings. Any features shown in the drawings are not necessarily drawn to scale.

[0019] Figure 1 is a graph illustrating changes in corneal sensation in rats after topical application of ambroxol or anesthetics.

[0020] Figure 2 is a graph illustrating the assessment of postoperative ocular pain following topical application of ambroxol by the rat eye rub assay.

[0021] Details

[0022] Overview

[0023] Various aspects of the present disclosure relate to methods, formulations and compositions (e.g., compositions comprising the formulations) for alleviating or eliminating ocular pain in a subject, particularly pain in a peripheral nerve, including neuropathic ocular pain (NOP), and uses of the formulations and compositions for alleviating or eliminating ocular pain in a subject, particularly pain in a peripheral nerve, including neuropathic ocular pain (NOP). The disclosed formulations and related uses and methods are different from previous methods of treating ocular pain. Specifically, the formulations disclosed herein include compounds that are capable of inhibiting the repetitive firing and overexcitation of neuronal cells on the surface of the eye that studies have shown to be primarily responsible for signal transduction of inflammatory and neuropathic pain. The formulations for treating ocular pain provide partial preservation of sensation in the eye, such as corneal sensation, to prevent the subject from inadvertently poking, scratching or overtly rubbing the eye. In one or more aspects, the methods and formulations include the use of an agent that can specifically and selectively inhibit voltage-gated sodium nociceptors (Nav) 1.8 and is additionally useful for desensitizing peripheral pain nerve excitability, such as ambroxol (trans-4-(2-amino-3,5-dibromobenzylamino)-cyclohexanol) or a chemical derivative of ambroxol, such as a salt form of ambroxol.

[0024]

[0025] Ambroxol was originally identified as a mucolytic agent and is commonly used to treat respiratory diseases associated with thick or excessive mucus. However, there has been no previous teaching that ambroxol or its derivatives may be effective when topically applied to treat ocular pain, including NOP. The pharmacological characteristics of ambroxol or its derivatives related to safety of topical application to the ocular surface have never been disclosed previously.

[0026] As used herein, the term "analgesic" refers to a compound that has an analgesic effect and has been established for the treatment of pain. Compounds that have analgesic activity and have been established for the treatment of pain include, but are not limited to, opioids (e.g., fentanyl, morphine) and non-opioid analgesics, such as amide-based local anesthetics (e.g., lidocaine and bupivacaine), ester-based local anesthetics (e.g., tetracaine, proparacaine, and chloroprocaine), and NSAIDs. Ambroxol, although not known or considered an analgesic, has a selective analgesic effect as demonstrated in the present disclosure.

[0027] As used herein, the term "local anesthetic" refers to a compound that, when applied to a target local area of ​​the body, induces up to complete insensitivity to pain (e.g., complete suppression of pain) while not affecting sensation outside the target local area. Local anesthetics can induce nearly complete or up to complete loss of sensation in the target local area. Local anesthetics are a subset of analgesics and include amide-based anesthetics and ester-based anesthetics.

[0028] The term "tetrodoxin-resistant nociceptors" refers to a class of nociceptors (e.g., pain receptors) that cannot be effectively inhibited or blocked by the compound tetrodotoxin. An example of a tetrodotoxin-resistant nociceptor is the Nav1.8 nociceptor. The term "tetrodotoxin-sensitive nociceptor" refers to a class of nociceptors that are effectively blocked by the compound tetrodotoxin. An example of a "tetrodotoxin-sensitive nociceptor" is the Nav1.7 nociceptor.

[0029] The term "selective Nav1.8 inhibitor" refers to a compound that selectively inhibits Nav1.8 nociceptors relative to other sensor receptors. For example, ambroxol selectively blocks Nav1.8 nociceptors (a tetrodotoxin-resistant nociceptor) relative to tetrodotoxin-sensitive nociceptors. Therefore, ambroxol is a selective Nav1.8 inhibitor. Opioids, amide-based local anesthetics, ester-based local anesthetics, and NSAIDS do not have selectivity for Nav1.8 nociceptors over tetrodotoxin-sensitive nociceptors and are therefore not considered to be selective Nav1.8 inhibitors.

[0030] The term "peripheral desensitizing" or "peripheral desensitization" refers to retraining peripheral nerves, such as those in the eye, to make the nerves less sensitive to stimulation and / or to inhibit the dysfunctional, enhanced autonomic neuronal activity associated with NOP. Peripheral nerve desensitizers are compounds that can inhibit oversensitive peripheral nerves to effectively desensitize the peripheral nerves from an oversensitive state.

[0031] Voltage-gated sodium nociceptors (Nav) are important determinants of sensory neuron excitability: they are essential for the initial transduction of sensory stimuli, the electrical generation of action potentials, and the release of neurotransmitters from sensory neuron terminals. These channels play a key role in the development and maintenance of pain. Commonly used topical ophthalmic local anesthetics such as lidocaine, proparacaine, and tetracaine are effective due to their non-selective Nav inhibition.

[0032] As used herein, the terms "ambroxol derivative", "derivative of ambroxol" and "chemical derivative of ambroxol" refer to compounds derived from ambroxol, precursor compounds of ambroxol and salt forms of ambroxol. For example, the chemical derivative of ambroxol may include the acid addition salt ambroxol hydrochloride [trans-4-(2-amino-3,5-dibromobenzylamino)cyclohexanol hydrochloride] or an N-acylated derivative of ambroxol hydrochloride. In certain aspects, more than one form of ambroxol may be included in a single formulation. For example, in some embodiments, a formulation may include at least a first ambroxol derivative and at least a second ambroxol derivative.

[0033] The disclosed methods and formulations are demonstrated to be selective in the treatment of ocular pain components through animal studies, and the methods and formulations do not completely inhibit sensations, such as those on the ocular surface (e.g., touch or tactile sensations). The ability of the methods and formulations to selectively inhibit pain (including pain on the ocular surface) is advantageous to the subject, thereby providing pain relief to the subject while still enabling the subject to sense changes in the environment and at the ocular surface (e.g., being able to sense while relieving pain). Thus, the methods and formulations can reduce the risk of damaging the eye by enabling the subject to have some eye sensations to prevent the subject from inadvertently poking, scratching, or overtly rubbing the eye. In addition, the sensor function of the eye to changes in temperature, pH, and osmotic pressure (e.g., Figure 2 For example, the high osmotic pressure and increased cooling rate at the corneal surface that occurs as the overlying tear film thins by evaporation drives nociceptive activity that maintains basal tear secretion, which is essential for ocular surface tear homeostasis and eye health.

[0034] As used herein, "topical administration", "topical treatment", or treatment by a topically applied drug (e.g., a topical anesthetic) may refer to the application of a drug or formulation to an external surface of a subject (e.g., the cornea, skin, or epidermis). As used herein, "topical administration", "topical treatment", or treatment by a topically applied drug (e.g., a local anesthetic) may refer to topical administration, but may also refer to injection or other introduction into the body at the treatment site, where the administered drug has a local effect.

[0035] In some aspects, the preparation is used in combination with surgery or trauma of eyes. In embodiments, analgesics (e.g., local anesthetic lidocaine) can also be used on the surface or systemically. Analgesic compounds, particularly local anesthetics, affect a variety of neuron receptor types, and are highly effective for removing most (even if not all) physical sensations, including tactile sensation (touch), pain and pressure sensation. Topical anesthetics include but are not limited to tetracaine, proparacaine, chloroprocaine, lidocaine and bupivacaine of severe paralysis. The preparation can be used locally or systemically with the use of local anesthetics or analgesics, to continue to relieve pain and prevent postoperative injury. For example, in ophthalmic surgery where local anesthetics (e.g., lidocaine) are the main drugs used during surgery, the preparation can be used near the end of the operation, so that when the lidocaine of severe paralysis fails, the preparation continues to provide pain relief, while allowing the subject to feel the sensation of the eyes, to reduce the risk of patients stabbing or scratching eyes, ocular surface drying (drying up) or other external potential sources of damage.

[0036] As used herein, the terms ocular, ophthalmic, and optic are used interchangeably to define "of, around, or relating to the eye." The term ocular pain is an inclusive term that includes acute and chronic conditions of the eye, nociceptive or neuropathic pain, involving neural connections between the eye and the brain, involving cellular inflammation, damage, degeneration, or loss.

[0037] NOP should not be confused with the discomfort symptoms that merely describe many disease processes. On the contrary, it is caused and / or maintained by dysfunctional elements in the nociceptive system. In contrast to the normal somatic sensation "nociceptive pain", it is a unique disease entity in itself. The potential pathophysiology of neuropathic pain may be peripheral or central sensitization of the nervous system. NOP is common in diseases associated with ocular surface tissue damage, such as infection, trauma, various ophthalmic surgeries (including laser refractive surgery) and chronic severe ocular surface damage (such as limbal stem cell deficiency and chemical burn sequelae). Peripheral damage triggers complex changes in the central nociceptive system, which can lead to central sensitization, which enhances the sensitivity and responsiveness of brain areas involved in sensory processing. In some cases, these physiological reactions progress to central neuropathic pain.

[0038] Non-ocular conditions are also associated with NOP, including diabetes and small fiber peripheral neuropathy, trigeminal neuralgia, and inflammatory autoimmune conditions such as Sjögren's syndrome and systemic lupus erythematosus. Nociceptive pain (physiologically normal and protective pain) and neuropathic pain (physiologically abnormal pain) are not mutually exclusive and can coexist. Chronic pain often has a neuropathic component. Tear film abnormalities, anatomical problems, and / or ocular surface inflammation may cause changes in corneal nerve structure and function to cause NOP. However, it should be emphasized that NOP itself is a unique disease entity. The symptoms of NOP can range from devastating, persistent eye pain and severe sensitivity to light (e.g., photophobia) in the worst cases, to mild hyperalgesia (e.g., increased sensitivity to sensory pain and extreme reactions to pain) or dysesthesia (e.g., sensory distortion, especially tactile). NOP patients may have little or no signs of ocular surface tissue damage and usually respond poorly to conventional treatments. Patients with chronic neuropathic pain are characterized by higher healthcare utilization, a higher risk of comorbidities such as depression, anxiety, and sleep disturbances, and lower quality of life compared with patients with chronic non-neuropathic pain.

[0039] Although the exact mechanism of NOP generation has not been fully elucidated, input from overexcited peripheral neurons, especially Nav1.8, is critical for the development, regulation, and maintenance of NOP. Pathological conditions (i.e., nerve injury, inflammation) lead to overactivation and dysfunction of neurons and non-neuronal cells, ultimately leading to neuronal overexcitation, peripheral sensitization, and pain. Therefore, inhibiting the excessive activity of peripheral neurons could help reduce the risk factors that cause the development of NOP.

[0040] Neuropathic pain, including NOP, is usually not treated with analgesics such as topical or general anesthetics (opioids or non-opioids). In fact, topical anesthetics can be used to distinguish nociceptive ocular pain from NOP, especially in the case of central sensitization. The presence or worsening of persistent ocular surface pain after placing a drop of topical anesthetic on the ocular surface indicates the central component of the pain. Incomplete improvement of symptoms after topical anesthetic stimulation may indicate mixed peripheral and central etiologies. Although there is overlap in the treatment of nociceptive pain and NOP, the treatment of NOP aims to desensitize peripheral and / or central nervous system function. This treatment principle is further described in Harrison Dermer et al., A Review of Management Strategies for Nociceptive and Neuropathic Ocular Surface Pain. Drugs (2020) 80: 547–571; "Addressing the Pain of Corneal Neuropathy". American Academy of Ophthalmology., July 2010.

[0041] Because nerve damage and inflammation may originate from the ocular surface, conventional dry eye treatments, including artificial tears and autologous serum eye drops, have been used to attempt to specifically reduce peripheral irritation (not directly targeting pain). Other treatments for peripheral desensitization include bandage contact lenses and / or non-fenestrated scleral lenses, which can isolate the corneal surface from unwanted stimuli. To inhibit or modulate central sensitization, systemic use of gabapentin and tricyclic antidepressants have been used to blunt sensory nerve stimulation or the perception of nerve stimulation. Other adjunctive therapies include transcutaneous electrical nerve stimulation, periocular botulinum toxin, periocular nerve blocks, trigeminal nerve stimulation, intrathecal analgesic pumps, and even cognitive behavioral therapy.

[0042] Three types of nociceptor (pain) fibers are found within the cornea, including mechanoreceptors (~20% of the total sensory population), polymodal receptors (~70% of the total sensory population), and cold receptors (~10% of the total sensory population). Of all the members of the Nav family, Nav1.8 is specifically involved in neuropathic and inflammatory pain. Nav1.8 is preferentially expressed in polymodal fibers and is therefore expected to be present in approximately 70% of corneal nociceptors. Since Nav1.8 contributes to the repetitive firing and neuronal excitability associated with pain, it has been shown that inhibition of Nav1.8 may control pain transmission and modulate pain perception in vivo through effects on overexcited neurons.

[0043] Ambroxol selectively inhibits Nav1.8 rather than other calcium and sodium channels, and has a particularly high affinity for Nav1.8. For example, the potency of ambroxol in blocking Nav1.8 is about 40 times that of lidocaine. Although not previously used for specific treatment or inhibition of ocular pain, the selectivity of ambroxol to Nav1.8 nociceptors and the evidence showing the ability of ambroxol preparations to inhibit pain while not eliminating all corneal sensations herein make the composition containing ambroxol become an ideal preparation for treating, inhibiting and / or improving ocular pain, including NOP.

[0044] As used herein, the terms "treatment" and "prevention" are not intended to be absolute terms. In embodiments, treatment may refer to a confirmed disease, condition, or symptom of the disease or condition being reduced in severity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. In embodiments, if one or more symptoms of the subject's disease are reduced by 10% compared to a control, the method for treating the disease is considered to be treatment. Therefore, compared to natural or control levels, the reduction may be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any reduction between 10% and 100%. It is to be understood that treatment does not necessarily refer to the cure or complete ablation of a disease, condition, or symptom of the disease or condition. In embodiments, reference to reduction, alleviation or inhibition includes changes of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more compared to control levels, and these terms may include, but do not necessarily include, complete elimination. Treatment may refer to any delay in onset, improvement of symptoms, improvement of patients. The therapeutic effect may be compared to an individual or group of individuals not receiving treatment, or to the same patient at different times before or during treatment.

[0045] In one or more aspects, administration of an effective amount of the formulation results in a reduction in subjective symptoms (e.g., a reduction in eye pain) or an improvement in a quality of life measure. A quality of life measure may include a measure determined by a subject completing a quality of life survey. Examples of quality of life surveys include, but are not limited to, the SF-36 survey (Rand Corporation), PROMIS TM 、Neuro-QoL TM 、ASCQ-Me TM and NIH Toolbox TM, Brief Pain Inventory (BPI), and Brief Ocular Discomfort (BODI) questionnaires. Ocular pain can be quantified using several validated questionnaires, including but not limited to the Visual Analog Scale (VAS) pain assessment, the Ocular Surface Disease Index (OSD) and the Ocular Surface Disease Index (OCD). ) The Neuropathic Pain Symptom Inventory modified for the Eye (NPSI-Eye), the Ocular Pain Assessment Survey (OPAS), and the Defense and Veterans Pain Rating Scale (DVPRS) were included.

[0046] preparation

[0047] As discussed above, and in various aspects, compositions and formulations for treating, inhibiting, improving and / or preventing ocular pain in a subject, including nociceptive ocular pain and NOP, are disclosed. In embodiments, agents with high selectivity for Nav1.8 inhibition and potential for peripheral nerve desensitization may be formulated, such as drugs for treating, improving, inhibiting or preventing ocular pain. In some embodiments, the formulation is prepared as eye drops.

[0048] NOP can be defined as a condition characterized by positive or negative sensory signs, perceived pain that is disproportionate to the noxious stimulus, and / or unresponsiveness to analgesics. NOP is a well-known discomfort after any corneal surgery. This is primarily due to abnormal regeneration of damaged corneal nerve endings and abnormal connections with adjacent nerve endings, resulting in spontaneous activity. Tear hyperosmolarity and the resulting ocular surface inflammation can also trigger autonomous activity of corneal nerve endings. NOP may be present throughout the eye, or in a portion of the eye, including but not limited to the cornea and conjunctiva. NOP may occur in the absence of stimulation or in the presence of normally non-painful light stimulation (e.g., photoallodynia), burning sensation (e.g., from contact with normally mild chemicals), dryness, or a gritty sensation.

[0049] In various aspects, the subject can be any type of animal susceptible to or suffering from the indicated disease or disorder, including but not limited to mammals, reptiles, amphibians and birds. For example, the subject can be any type of mammal, including but not limited to humans, non-human primates, cats, dogs, rats, mice and livestock such as cattle, sheep, goats and pigs.

[0050] In various aspects, the preparation may include a selective Nav1.8 inhibitor and a peripheral nerve desensitizer (e.g., a Nav1.8 inhibitor that acts as a peripheral nerve desensitizer). For example, the composition, preparation, and method may include a Nav1.8 selector, including but not limited to ambroxol. The use of ambroxol may include any form or salt of ambroxol, including but not limited to ambroxol hydrochloride or the free acid of ambroxol.

[0051] In various aspects, based on the total weight or volume (w / w, w / v) of the preparation, the concentration of the selective Nav1.8 inhibitor and the peripheral nerve desensitizer such as ambroxol or the ambroxol salt in the preparation can be 0.001% by weight to 20% by weight, 0.01% by weight to 10% by weight, 0.05% by weight to 5.0% by weight, 0.1% by weight to 2.5% by weight, 0.2% by weight to 1% by weight, and 0.3% by weight to 0.7% by weight. For example, based on the total weight (w / w) of the preparation, the total concentration of the agent such as ambroxol or the ambroxol salt can be about 0.5% by weight. In another example, based on the total volume (w / v) of the preparation, the total concentration of the agent such as ambroxol or the ambroxol salt can be 0.001% by weight to 3.0% by weight.

[0052] In various aspects, the formulation includes a buffer. The buffer may include any type of buffer system, including but not limited to borate, citrate, Tris-HCL, phosphate, bicarbonate, lactate and sodium buffers. The buffer may include any pharmaceutically acceptable salt, acid or base compatible with administration to the ocular surface, including but not limited to boric acid, sodium borate, sodium citrate, potassium phosphate, potassium chloride and sodium chloride. For example, the buffer may include a borate buffer, which includes boric acid and sodium borate.

[0053] "Pharmaceutically acceptable salts" refers to salts of compounds that are pharmaceutically acceptable as defined above and that have the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids or with organic acids. Pharmaceutically acceptable salts also include base addition salts, which can be formed when the acidic protons present are capable of reacting with inorganic or organic bases. "Pharmaceutically acceptable" refers to those that can be used to prepare pharmaceutical compositions that are generally safe, non-toxic and not undesirable biologically or otherwise, and includes those that are acceptable for veterinary as well as human pharmaceutical use.

[0054] In various aspects, the preparation includes cyclodextrin. Cyclodextrin is a cylindrical oligosaccharide with a lipophilic central cavity and a hydrophilic outer surface. Cyclodextrin can form a complex with a lipophilic drug to seal the drug in the lipophilic cavity, which can enhance the solubility and absorption properties of the preparation. The preparation can include any cyclodextrin type (e.g., α, β, γ or hydroxypropyl γ-cyclodextrin) and cyclodextrin of any size. For example, cyclodextrin can have a molecular weight of 800 to 2400 g / mol, 1000 to 2000 g / mol, 1200 to 1800 g / mol or 1200 to 1600 g / mol. The preparation can also include other polymers and polymer types, including but not limited to polyethylene glycol (e.g., a polyethylene glycol with a molecular weight of about 300 g / mol), polysaccharide dextran (e.g., Dextran T500 sold by Pharmacosmos). TM , which has an average molecular weight of about 500,000 g / mol), povidone polyvinylpyrrolidone (PVP) (e.g., PVP K30), and cellulose ethers, such as carboxymethylcellulose (CMC) Methocel sold by DuPont TM and Methocel E4M TM .

[0055] In various aspects, the formulation is prepared to have a specific osmotic pressure concentration or a molar osmotic pressure concentration within a specific range. For example, the formulation can be prepared to have a molar osmotic pressure concentration within the range of 270 to 310, 270 to 320, or 280 to 320 mOsm / liter. For example, the formulation can have a molar osmotic pressure concentration of approximately 280, 290, 300, 310, or 320 mOsm / liter.

[0056] In various aspects, the formulation can be prepared to have a specific pH or a pH within a specific range. For example, the formulation can be prepared to have a pH within the range of 6.5 to 7.4, 6.5 to 7.0, or 6.8 to 7.4. For example, the formulation can have a pH of approximately 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, or 7.5.

[0057] In various aspects, the formulation can be prepared in any type or mode for treating the eye. For example, the formulation can be included in an eye drop formulation or an ointment (e.g., an ophthalmic ointment). In another example, the formulation can be impregnated with a soluble biopolymer to be slowly released into the tear film as an ocular insert applied to the eye (e.g., topical administration). For example, the biopolymer can include a hydrogel.

[0058] Topical administration refers to administration by applying the formulation to the epidermis (e.g., eyelids) or ocular surfaces (e.g., cornea and conjunctiva). These types of compositions are typically in the form of solutions, gels, drops, creams, ointments, suspensions, dispersions, nanoparticle dispersions, emulsions, microemulsions, liposomes, pastes, and sprays. Topical administration of drugs acting on ocular pain has undoubted advantages in clinical practice, including reduced or absent systemic side effects due to low or no systemic absorption, relatively few drug-drug interactions, ease of use and dosage, avoidance of first-pass metabolism, improved patient compliance, and direct access to the target.

[0059] The frequency of surface application to the subject (for example, human or animal) can vary from patient to patient.For example, in some cases, the disclosed preparation can be applied at a frequency of once every ten minutes or at a frequency of once a day.The preparation can be applied once, twice, three times or more in a time period of one day, two days, three days, four days, five days or more than five days.In some embodiments, the disclosed preparation can also include an extended release vehicle, such as a biocompatible polymer, which is dissolved in a carrier or itself is impregnated with ambroxol to retain ambroxol and slowly release it into the tear film or on the ocular surface, preferably for up to six months or longer extended release period.The biocompatible polymer can be biodegradable or non-biodegradable, depending on the desired use and the application schedule.Exemplary biocompatible polymers that can be used as extended release vehicles in the disclosed preparation include but are not limited to poly 2-hydroxyethyl methacrylate (p-HEMA hydrogel), poly (lactic acid-co-glycolic acid) (PLGA), polycaprolactone (PCL), hydroxypropyl cellulose, anecortave acetate (AnA), gelatin and / or collagen. In some cases, the addition of an extended release vehicle can allow for less frequent application while still providing therapeutic efficacy for ocular pain (including NOP). For example, the biopolymer may include a hydrogel. Other articles, formulations, and formulation components may include those listed in U.S. Patent No. US10,265,280, which is incorporated herein by reference in its entirety.

[0060] In one or more aspects, the disclosed preparations may also include one or more additives. The additives that may be included in the disclosed preparations include, but are not limited to, mitigants, preservatives, emollients, ionic species, pH regulators, and other possible additives. Exemplary mitigants that may be used in the disclosed preparations include, but are not limited to, glycerol, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, dextran 70, gelatin, polyethylene glycol 300, polyethylene glycol 400, polysorbate 80, polyvinyl alcohol, povidone, cyclodextrin, etc. Examples of preservatives that may be used in the disclosed preparations include benzalkonium chloride and chlorobutanol. Emollients may include lanolin preparations, various mineral oils, ω3, paraffin, petroleum, and wax. In some embodiments, zinc and / or sodium ions may be included in the disclosed preparations as ionic species. Examples of pH regulators that may be used include citrate buffers (e.g., sodium citrate), borate buffers (e.g., sodium borate), and other acidic or alkaline compounds. The formulation may include one or more chelating agents, including but not limited to EDTA (e.g., disodium ethylenediaminetetraacetic acid) and EGTA (e.g., ethylene glycol tetraacetic acid). The formulation may include one or more surfactants, including but not limited to sodium lauryl sulfate. Many configurations and variations of additives may be used in the disclosed formulations.

[0061] Another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of ambroxol or a pharmaceutically acceptable amount of ambroxol and a pharmaceutically acceptable carrier. The term "therapeutically effective amount" refers to the amount of a compound that is effective in producing a desired therapeutic response in a particular patient suffering from a disease or disorder (e.g., ocular pain, including NOP).

[0062] The term "therapeutically effective amount" or "effective amount" includes an amount of a compound of the present disclosure or a pharmaceutically acceptable salt or stereoisomer thereof that induces a positive change in the disease or disorder to be treated (e.g., relieves eye pain) or is sufficient to prevent the development or progression of a disease or disorder or to alleviate to some extent one or more symptoms of the disease or disorder treated in a subject when administered. For example, for a given parameter, a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90% or at least 100%. The therapeutic efficacy can also be expressed as a "fold" of the increase or decrease. For example, a therapeutically effective amount may have an effect of at least 1.2 times, 1.5 times, 2 times, 5 times or more times that of a control. If after a period of time, the effective amount of the compound no longer shows a reduction in the symptoms of the disorder or condition (e.g., eye pain) as described above, the compound is considered to be no longer effective. For example, after the co-administered analgesic is no longer effective, the formulation can still continue to treat the subject's eye pain.

[0063] As is known in the art, the term "pharmaceutically acceptable carrier," "carrier" or medium refers to any pharmaceutically acceptable material, medium, composition or vehicle suitable for administration to a subject. Suitable carriers may include, for example, liquids (aqueous and non-aqueous analogs, and combinations thereof), solids, encapsulating materials, gases and combinations thereof (e.g., semisolids) and gases, which function to carry or transport a compound from one organ or part of the body to another organ or another part of the body. The term may also refer to reagents, buffers, cells, compounds, materials, compositions and / or dosage forms that are not only compatible with other agents to be administered therapeutically, but are also suitable for use in contact with tissues of humans and animals without excessive toxicity, irritation, allergic response or other complications, commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment.

[0064] In various fields, the preparation can include a pharmaceutically acceptable excipient. The term "pharmaceutically acceptable excipient" refers to a material that helps the active agent to be used and absorbed by the subject, and can be included in the composition of the present invention without causing significant adverse toxicological effects to the patient. The non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, saline solution, lactated Ringer's solution, normal sucrose, normal glucose, adhesives, fillers, disintegrants, lubricants, coatings, saline solutions (such as Ringer's solution), alcohol, oil, gelatin, carbohydrates, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidone and coloring agents. Such preparations can be sterilized, and if necessary, with adjuvants, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts, buffers, coloring agents and / or aromatic substances for affecting osmotic pressure. Those skilled in the art will recognize that other pharmaceutical excipients can be used for the present invention.

[0065] method

[0066] In various aspects, as disclosed herein, the preparation is applied to treat eye pain using one or more of the above-mentioned preparations or preparation components, including NOP. In certain aspects, the preparation is applied to the subject's eyes and eyelids, and the subject includes any type of animal (e.g., human) as described in detail above. In various aspects, the preparation includes a selective Nav1.8 inhibitor and a peripheral nerve desensitizer. For example, the Nav1.8 inhibitor compound ambroxol and / or the salt form of ambroxol acts as a peripheral nerve desensitizer in the treatment of NOP. The concentration of ambroxol and / or the salt form of ambroxol in the preparation can be within the range or approximate value of any concentration as described in detail above. The preparation may also include any component, buffer, carrier, cyclodextrin, polymer, surfactant, preservative or salt as described in detail above. One embodiment is a method for treating eye pain in a subject by applying the above-mentioned preparation including a selective Nav1.8 inhibitor and a peripheral nerve desensitizer (e.g., a selective Nav1.8 inhibitor acting as a peripheral nerve desensitizer) to the ocular surface of a subject suffering from eye pain. In an embodiment, the selective Nav1.8 inhibitor and the peripheral nerve desensitizing agent comprises ambroxol and / or a salt form of ambroxol.

[0067] In one or more aspects, the formulation is administered in connection with ophthalmic surgery. Ophthalmic surgery may include any type of surgical intervention involving the eye, including but not limited to LASIK (Laser-Assisted In Situ Keratomileusis), PRK (Photorefractive Keratectomy), LASEK (Laser-Assisted Subepithelial Keratectomy), Epi-LASIK (Epithelial Laser In Situ Keratomileusis), wavefront-guided LASIK, wavefront-guided PRK, PTK (Phototherapeutic Keratectomy), intracorneal ring segments (ICRS) implantation, corneal cross-linking, conductive keratoplasty (CK), INTACS (Intrastromal corneal ring segments) implantation, corneal chromotherapy (keratomileusis), keratoconjunctivitis (keratoconjunctivitis), keratoconjunctivitis, keratoconjunctivitis, keratoconjunctivitis, keratoconjunctivitis, keratoconjunctivitis, keratoconjunctivitis, keratoconjunctivitis, keratoconjunctivitis, keratoconjunctivitis, keratoconjunctivitis, keratoconjunctivitis, keratoconjunctivitis, keratoconjunctivitis, keratoconjunctivitis, keratoconjunctivitis, keratoconjunctivitis, keratoconjunctivitis, keratoconjunctivitis, keratoconjunctivitis, keratoconjunctivitis, keratoconjunctivitis, keratoconjunctivitis, keratoconjunctivitis, keratoconjunctivitis, The invention relates to the treatment, prevention, suppression or amelioration of ocular pain, including NOP associated with ophthalmic surgery.

[0068] In one or more aspects, the administration of the preparation is related to eye trauma or sequelae involving severe damage to the ocular surface or eyeball wall, such as corneal abrasion or erosion, infiltration, perforation, foreign matter, eyeball rupture, chemical burns (e.g., alkali or acid splashed into the eye) or thermal damage to the ocular surface. In one or more aspects, the administration of the preparation is related to the treatment of eye infections (e.g., bacteria, fungi, viruses and parasites), such as in infectious keratitis. For example, the preparation can be applied to subjects with infections (e.g., from herpes simplex, herpes zoster virus or acanthamoeba) that can cause intractable eye pain and are particularly prone to developing into NOP. In one or more aspects, the administration of the preparation is related to the patient's condition, which is related to or causes acute or chronic inflammation, such as recurrent corneal erosion / epithelial basement membrane dystrophy, ocular surface diseases (e.g., Sjögren's syndrome, autoimmune / connective tissue disease, Steven-Johnson syndrome, pemphigoid), limbal stem cell deficiency and uveitis of all causes.

[0069] In some aspects, the use of the method and the preparation or composition further comprises administering or co-administering an analgesic, such as an opioid (e.g., fentanyl and morphine), or a non-opioid analgesic, such as an amide-based local anesthetic (e.g., lidocaine and bupivacaine), an ester-based local anesthetic (e.g., tetracaine, proparacaine and chloroprocaine), or an NSAID that relieves pain. For example, an analgesic can be administered during eye treatment, such as eye surgery, or after an eye injury or eye surgery, where the preparation has also been administered. For example, the preparation can be topically applied to the surface of the eye before, approximately at the same time, or after the administration of the analgesic. The preparation can also be topically administered before the onset of postoperative pain or eye injury pain, where the onset of postoperative pain or eye injury pain has been delayed by the administration of an analgesic. For example, after eye surgery using a local anesthetic, ambroxol is administered so that when the local anesthetic fails, ambroxol is still effective in relieving pain while retaining some sensation of the eye. In another example, following an eye injury where a local anesthetic may have been initially used to relieve severe eye pain (e.g., while the patient is being supervised by personnel to be careful about the subject touching or scratching the eye), ambroxol is administered so that when the local anesthetic wears off, the ambroxol remains effective in relieving pain while preserving some sensation in the eye.

[0070] When administered with the formulation, the analgesic may be administered topically or systemically. For example, a subject may receive an opioid (e.g., fentanyl) intravenously while receiving the formulation applied to the surface of the eye. In another example, a subject may receive a non-opioid local anesthetic (e.g., intramuscular lidocaine) while receiving the formulation applied to the surface of the eye. In another example, a subject may receive a local anesthetic in the form of eye drops containing proparacaine while also receiving the formulation applied to the surface of the eye.

[0071] By administering the formulation at a time point before other analgesics fail (e.g., the formulation prolongs pain relief after analgesics are administered but before they fail), the formulation continues to provide pain relief (e.g., NOP relief) while still allowing the subject to experience certain key sensations of the ocular surface, such as a sense of coolness and hyperosmotic pressure. Analgesics administered prior to administration of the formulation may include any opioid and non-opioid analgesics for eye pain, including but not limited to tetracaine, proparacaine, lidocaine, or bupivacaine. The formulation may or may not include other analgesics.

[0072] In one or more aspects, the formulation is administered for ocular trauma or other eye pain unrelated to surgery. For example, the formulation can be used for ocular trauma caused by physical stress (e.g., corneal abrasions, chemicals, and burns). The formulation can also be administered to a subject to treat NOP associated with trauma and / or NOP of unknown cause.

[0073] In one or more aspects, the formulation is used in combination with other classes of analgesics (e.g., non-opioids or opioids) following an ocular traumatic event (e.g., corneal abrasions, ocular contusions, ocular punctures, ocular abrasions). For example, the formulation can be used before, during, or after administration of other classes of analgesics. For example, following an ocular traumatic event, the formulation can be used after administration of an analgesic (e.g., lidocaine or NSAID).

[0074] In one or more aspects, the preparation can be applied to the surface or systemically within 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 15 minutes, 10 minutes, 5 minutes, 2 minutes, 1 minute, 30 seconds or 10 seconds of the analgesic of the experimenter being subjected to ocular trauma or receiving ophthalmic surgery or receiving other classifications. For example, the experimenter can first accept analgesic (such as lidocaine) after eye puncture, then accept the preparation containing ambroxol (as analgesic begins to lose efficacy) after applying analgesic one hour. In another example, when the preparation includes extended release vehicle, the preparation can be applied to the surface of the frequency at least once a day to once a week, or once a month to once every six months. The frequency applied on the surface can be determined by many considerations, including the symptom relief level provided, the pain relief experienced and other relevant health considerations, such as possible drug interactions.

[0075] In one or more aspects, the preparation is applied using any desired technology. For example, the preparation can be an eye drop applied manually by the user. In other cases, the preparation can be applied directly to the desired area of ​​the eye or around the eye as a gel or ointment, such as using a swab or other type of applicator. In some aspects, the disclosed preparation can be delivered using a device designed for immediate preparation release or extended preparation release. For example, the preparation can be delivered using one or more of the following devices: an external pump, contact lenses, punctal plugs, mucoadhesive tablets, pills, capsules, pellets, granules, plasters, ocular insert devices, strips placed on the eyelid, conjunctiva or cornea, conjunctival inserts or depots, subconjunctival, subtenon fascia and intravitreal injection, or another suitable type of device. For example, the device can be configured to apply the preparation to a subject.

[0076] In one or more aspects, a percentage of ocular sensation, including corneal sensation, is retained after administration of the formulation (e.g., the formulation provides partial retention of corneal sensation in the eye). For example, after the formulation is applied to the subject's eye, the subject retains some corneal sensation even when the effect of the formulation is at its maximum. For example, if the maximum effect of the formulation in reducing pain is 5 minutes after the formulation is applied to the eye, the subject will still feel corneal sensation at 5 minutes. The subject's ability to sense the cornea is a safety advantage because the subject's complete loss of physical sensation, such as when a local anesthetic (e.g., proparacaine) is applied, may cause the subject to unknowingly damage the eye by rubbing, stabbing, or scratching. Retaining ocular sensation to changes in pH, temperature, and osmolarity is also physiologically necessary in the maintenance of ocular surface health and vision because high osmotic pressure and increased cooling rates at the ocular surface, such as the corneal surface, drive nociceptive activity that maintains basal tear secretion. The maximum eye sensation retained or preserved after applying the preparation can be equal to or greater than 1.0, 2.0, 3.0, 4.0, 5.0, 7.5, 10.0, 12.5, 15.0, 17.5, 20.0, 25.0, 30.0, 35.0, 40.0, 45.0 or 50%. The maximum eye sensation retained or preserved after applying the preparation can be in the range of 5% to 50%, 10% to 30%, 10% to 20%, 5% to 15% and 15% to 20%. For example, a preparation that reduces the amount of eye sensation by 90% can be applied to a subject who has undergone eye surgery, and the eye sensation (e.g., tactile sensation) preserved in the eye is at least or about 10%. In another example, a preparation that reduces the amount of corneal sensation by 85% can be applied to a subject who has undergone eye surgery, and the corneal sensation (e.g., tactile sensation) preserved in the eye is at least or about 15%. In another example, a formulation that reduces the amount of corneal sensation by 80% can be administered to a subject who has undergone ocular surgery, with corneal sensation (eg, tactile sensation) preserved at least or about 20% in the eye.

[0077] In some aspects of the disclosure, the methods, compositions, and formulations may be defined in any of the following numbered paragraphs:

[0078] 1. Use of a preparation for treating nociceptive eye pain and / or neuropathic eye pain in a subject, comprising:

[0079] topically administering to the ocular surface of a subject suffering from nociceptive ocular pain and / or neuropathic ocular pain an effective amount of a formulation comprising a selective Nav1.8 inhibitor, wherein the Nav1.8 inhibitor is a peripheral nerve desensitizer,

[0080] The Nav1.8 inhibitor is ambroxol and / or an ambroxol derivative.

[0081] 2. The use of paragraph 1, wherein administration of the formulation provides partial preservation of sensation in the eye.

[0082] 3. The use of paragraph 2, wherein the partial retention of sensation in the eye comprises retention of at least 10% of the sensation in the eye.

[0083] 4. The use of paragraph 2, wherein the partial retention of sensation in the eye comprises retention of at least 20% of the sensation in the eye.

[0084] 5. The use according to any one of paragraphs 1 to 4, wherein the weight percentage of the ambroxol and / or the ambroxol derivative is 0.001% to 10% based on the total weight or total volume of the preparation.

[0085] 6. The use according to any one of paragraphs 1 to 5, wherein the weight percentage of the ambroxol and / or the ambroxol derivative is 0.05% to 2.0% based on the total weight or total volume of the preparation.

[0086] 7. The use according to any one of paragraphs 1 to 6, wherein the formulation further comprises cyclodextrin.

[0087] 8. The use according to any one of paragraphs 1 to 7, wherein the administration of the formulation is associated with ocular trauma or ophthalmic surgery.

[0088] 9. The use of any one of paragraphs 1 to 8, further comprising administering an analgesic.

[0089] 10. The use of paragraph 9, wherein the preparation is topically applied to the ocular surface prior to administration of the analgesic.

[0090] 11. The use of paragraph 9, wherein the formulation is topically administered at about the same time as the analgesic is administered.

[0091] 12. The use of paragraph 9, wherein the preparation is topically administered after administration of the analgesic.

[0092] 13. The use according to paragraphs 9-12, wherein the preparation is topically administered before the onset of postoperative pain or ocular trauma pain, wherein the onset of postoperative pain or ocular trauma pain has been delayed by administration of analgesics.

[0093] 14. The use of paragraphs 9-13, wherein the formulation continues to treat nociceptive and / or neuropathic ocular pain after the effect of the analgesic is no longer effective.

[0094] 15. The use of paragraphs 9-15, wherein the analgesic comprises tetracaine, proparacaine, chloroprocaine, lidocaine or bupivacaine.

[0095] 16. The use of any of paragraphs 9-15, wherein the analgesic comprises an opioid.

[0096] 17. The use of any one of paragraphs 9-15, wherein the analgesic comprises a nonsteroidal anti-inflammatory drug.

[0097] 18. The use of any of paragraphs 1-17, wherein the formulation is administered within 60 minutes of the subject undergoing ocular trauma or ophthalmic surgery.

[0098] 19. The use of any of paragraphs 1-17, wherein the formulation is administered within 20 minutes of the subject undergoing ocular trauma or ophthalmic surgery.

[0099] 20. The use of any of paragraphs 1-17, wherein the formulation is administered within 5 minutes of the subject undergoing ocular trauma or ophthalmic surgery.

[0100] 21. The use of paragraphs 1-20, wherein a device provides for administration of the formulation.

[0101] 22. The use according to any one of paragraphs 1 to 21, wherein the formulation comprises a biocompatible polymer.

[0102] 23. The use of paragraph 22, wherein the ambroxol and / or the chemical derivative of ambroxol is impregnated in the biocompatible polymer.

[0103] 24. The use according to paragraph 22 or 23, wherein the biocompatible polymer is dissolved in a carrier.

[0104] 25. The use of any of paragraphs 22-24, wherein the biocompatible polymer comprises poly (2-hydroxyethyl methacrylate) (p-HEMA hydrogel), poly (lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), hydroxypropyl cellulose, anecortave acetate (AnA), gelatin and / or collagen.

[0105] 26. The use according to any one of paragraphs 1 to 25, wherein the formulation further comprises an additive, wherein the additive is a demulcent, a preservative, an emollient or a pH adjuster.

[0106] 27. The use of any of paragraphs 1-26, wherein administration of an effective amount of the formulation results in a reduction in subjective symptoms or an improvement in a quality of life measure.

[0107] 28. Use of the formulation of paragraph 1 in the preparation of a medicament for treating nociceptive ocular pain and / or neuropathic ocular pain in a subject, wherein the treatment comprises administering an effective amount of the formulation to the ocular surface of the subject.

[0108] 29. A formulation for use in paragraph 1, comprising a composition comprising:

[0109] Based on the total weight or volume of the preparation, 0.01% to 10% by weight of ambroxol and / or ambroxol derivatives; and cyclodextrin. Example

[0110] The following examples are illustrative and should not be construed as limiting the scope of the claimed subject matter.

[0111] Example 1: Preparation of Selective Nav1.8 Inhibitors and Peripheral Nerve Desensitizers

[0112] The pharmaceutical properties of ambroxol and its derivatives are independent of other ingredients contained in the preparation. The combination of various ingredients will not significantly affect the pharmaceutical properties of ambroxol and its derivatives.

[0113] Tables 1 and 2 disclose exemplary formulations for treating ocular pain, including NOP:

[0114] Table 1

[0115]

[0116]

[0117] *Based on the total weight or volume of the formulation; the pH of the formulation is adjusted to 6.5-7; the osmolarity is in the range of 270 to 320 mOsm / L, particularly at about 290 mOsm / L.

[0118] Table 2

[0119] step Components %concentration* 1 Anhydrous potassium dihydrogen phosphate 0.130-0.260 2 Ambroxol HCl 0.270-0.540 3 Potassium hydrogen phosphate, trihydrate 0.280-0.510 4 Potassium chloride 0.760 5 Alginate (Sigma) 0.500 Or PVPK30 0.2-1.0 Or CMC 0.2-1.5 Purified water QS to 100% w / w

[0120] *Based on the total weight or volume of the formulation, pH = 6.8-7.4, Osmolarity = 270-320 mOsm / L.

[0121] The concentrations of the components of formulations containing ambroxol can vary. Table 3 details the ranges of formulation components for the treatment of ocular pain, including nociceptive ocular pain and / or NOP:

[0122] Table 3

[0123]

[0124]

[0125] *Based on the total weight or volume of the formulation

[0126] Example 2: Partial preservation of corneal sensation using a formulation containing ambroxol

[0127] Acute eye pain, defined as pain that lasts for several days, is usually caused by trauma (including eye surgery), infection, and inflammation. Chronic pain, which usually lasts longer than 2 weeks, is usually caused by chronic diseases that cause inflammation and damage to the ocular surface, such as dry eye disease, herpetic keratitis, and after laser refractive surgery. Symptoms include discomfort, burning, pain, itching, and even photophobia. Eye pain can have a significant impact on a person's quality of life, productivity, and ability to work.

[0128] To treat ocular pain, opioid and non-opioid local or topical anesthetics can be used in various ocular surgeries to provide temporary relief of pain, but doctors discourage the prescription of topical anesthetics (e.g., proparacaine or tetracaine) or NSAIDs due to their high adverse reaction rates. Unsupervised use of topical anesthetics or NSAIDs can cause corneal ulcers, infections, and even perforations. Oral opioid or non-opioid pain medications also cause serious systemic side effects, such as overdose and drug-drug interactions, and can sometimes lead to dependence and abuse.

[0129] Studies have shown that ambroxol can stimulate water and mucin secretion across the conjunctiva and has anti-inflammatory properties suitable for treating dry eye. In addition, ambroxol is an inhibitor of neuronal Nav nociceptors, preferably Nav1.8, responsible for sending inflammatory and neuropathic pain signals, and therefore has an analgesic effect. The ability of ambroxol to retain certain sensor functions of the cornea is particularly promising because it has a much higher safety profile.

[0130] The ability of the ambroxol-containing formulation to partially preserve corneal sensation in rats was shown Figure 1 The effect of ambroxol preserves some sensation in the cornea, which may be due to its selectivity for certain Nav nociceptors, especially Nav1.8. In addition, other nociceptors such as transient receptor potential vanilloid type 1 (TRPV1) are also involved in pain perception and transmission. So far, there is no data indicating that ambroxol binds to TRPV1 receptors.

[0131] The nervous system of the ocular surface is more unique than any other part of the body in its primary role of protecting, maintaining and restoring the optical tear layer. In order to meet this survival need, the cornea has evolved into the most powerful, sensitive and complex pain system that cannot be matched by any other part of the body. Due to this uniqueness of the cornea, it is difficult to determine the effectiveness of drugs applied to the ocular surface without experiments. The applicability, efficacy and safety of these drugs cannot be predicted or assumed. For example, it is well known that the efficacy of analgesics or local anesthetics in other parts of the body cannot be simply replicated on the ocular surface and applied directly to the eye to control ocular pain. In the case of non-selective sodium channel blocker anesthetics, without considering their toxicity to the cornea, if this delicate sensor network in the cornea is completely blocked (for example, Figure 1If the ocular surface is not treated with proparacaine in the ocular surface, it will lose its ability to maintain adequate basal tear secretion, respond appropriately to external insults, and fail to protect the eye. The ability to sense foreign matter (e.g., touch and pain), temperature changes, or changes in tear chemistry (e.g., pH and osmotic pressure) and respond by avoiding and / or increasing tear secretion is extremely critical in protecting the eye and vision. Our discovery of the unexpected pharmacological properties of ambroxol in partially preserving corneal sensation constitutes an important safety feature for topical administration, especially for ocular pain control. This new discovery is unique and, to our knowledge, has not been previously disclosed.

[0132] In this example, 0.3% and 0.5% ambroxol HCl solutions were prepared with PEG 300MW, dextran T500 and borate buffer as the main ingredients. Commercially available 0.5% proparacaine HCl was used as a topical anesthetic control. Corneal sensation was assessed by a Cochet-Bonnet aesthesiometer at different time points (e.g., 0 minutes, 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, or 4 hours) before and after a drop of 0.5% proparacaine, 0.5% or 0.3% ambroxol was applied to the rat eye. The Cochet-Bonnet aesthesiometer measures the tactile sensation of the cornea. At each time point, corneal tactile measurements were performed twice for each eye, and the average was taken as the final reading. Note that even when the effect of the ambroxol-containing formulation was at its maximum (5-15 minutes), a minimum of 15% of the total corneal sensation was retained in the two ambroxol treatment groups, and a higher level of sensation retention was maintained throughout the duration of the drug effect (approximately 4 hours) ( Figure 1 ).

[0133] Example 3: Selective inhibition of peripheral neuronal excitability by preparations containing ambroxol

[0134] In the case of making minor modifications to the established rat NOP model, eye pain is caused by removing the corneal epithelium (Epi-off) under general anesthesia. 2MNaCl saline (different from the 5M NaCl used in previous studies) is used to trigger peripheral neuronal excitation in response to high osmotic pressure, while minimizing the potential intrinsic stimulation of 5M NaCl to the cornea. Then, each rat is given 1 hour to allow full recovery from anesthesia before subsequent research steps. Compared with before epithelial removal (Epi-on), the sensitivity of the cornea to pain (rubbing eye count / minute) in response to 2MNaCl after surgery (Epi-off) is significantly increased. Then, a drop of 0.5% ambroxol is applied to the ocular surface, and the eye rubbing behavior in response to 2MNaCl is continuously monitored by video recording at various time points (e.g., 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours or 5 hours), and compared with a control group treated with a drop of vehicle buffer solution without ambroxol. After treatment with 0.5% ambroxol, a significant reduction in eye rubbing counts / minute was recorded, which lasted for at least 4 hours, while sensitivity to hyperosmolarity of the ocular surface was clearly preserved. This suggests that ambroxol can inhibit peripheral pain signaling activity, thereby inhibiting pain signal transduction to brain centers in response to hyperosmolarity.

[0135] Even at the maximum effect of the ambroxol-containing formulation (up to 30 minutes after application), it was demonstrated that neurons at the ocular surface were sensitive to hyperosmolarity and these signals were centrally transmitted to the brain (triggering increased eye rubbing behavior compared to Epi-on). This observation revealed a significant reduction in pain signaling activity (compared to the vehicle buffer control group), suggesting the potential of peripheral nerve desensitization in the treatment of NOP. When the same study was performed using 0.5% proparacaine HCl, at its maximum effect (5 minutes), no significant changes were seen in the eye rubbing counts before surgery (Epi-on) and after surgery (Epi-off) (data not shown), suggesting non-selective inhibition of neuronal excitability at the ocular surface. Due to its short duration of action, the proparacaine group ( Figure 2 ).

[0136] exist Figure 2The ability of a preparation containing ambroxol evaluated by an eye rub assay to reduce postoperative ocular pain was demonstrated in. Here, the preparation showed 1) retention of the ocular surface's sense of elevated osmotic pressure; and 2) inhibition of peripheral neuronal pain signal activity to reduce centrally emitted pain signals to the brain. This inhibition of peripheral neuronal excitability suggests that ambroxol has great potential as a peripheral nerve desensitization drug, especially for NOP. These results indicate that when applied topically on the ocular surface, a preparation containing ambroxol can inhibit peripheral nerve sensory excitability, possibly by preferentially blocking Nav1.8 nociceptors, and therefore has the potential to become a peripheral nerve desensitization drug for NOP. Nav1.8 nociceptors in neural tissue contribute to repetitive discharges and neuronal excitability, and are significantly associated with neuropathic and inflammatory pain (Bird EV et al., Mol Pain. 2013; Daou I et al., eNeuro. 2016).

[0137] Ambroxol has the same level of binding affinity for Nav1.7 nociceptors as lidocaine. However, ambroxol is 40 times more potent than lidocaine in binding to Nav1.8 nociceptors. Although the selective blocker ambroxol appears to be less effective in treating ocular pain, it is this unique pharmacological property that gives ambroxol a previously unknown safety advantage for ocular pain control. For the same reason, the non-selective blocker lidocaine may not be suitable for peripheral nerve desensitization in the treatment of NOP due to its low efficacy against the dysfunctional, overexcited Nav1.8 nociceptors involved in NOP. In order to achieve a similar effect, the concentration of lidocaine must be raised to such a high level that the result may pose an unacceptable safety risk to the ocular surface tissue.

[0138] These results also demonstrate the ability of the formulation to retain key physiological sensations, including hyperosmotic pressure. This ability of the formulation to retain multiple physiological sensations constitutes a novel safety profile of ambroxol when used topically for ocular pain control (nociceptive and neuropathic pain).

[0139] The rat eye-wipe assay is an established animal behavioral and neurophysiological tool for assessing corneal sensitivity to noxious stimuli (Price TJ et al., Br. J. Pharmacol.). Increased corneal sensitivity was demonstrated in male rats after lacrimal gland removal, which correlated with eye-wiping behavior in response to hypertonic saline (5M NaCl) (Meng ID et al., Invest. Ophthalmol. Vis. Sci. 2015).

[0140] In general, the tactile sensation at the cornea is partially preserved ( Figure 1 ) and preserve other key corneal sensations, especially those to high osmotic pressure (e.g. Figure 2 The discovery of (shown in) constitutes an unexpected result for ambroxol. The property that ambroxol partially retains the sense of touch was previously unknown and provides a newly discovered safety feature for ambroxol. Therefore, this application of ambroxol for ocular pain control in general has been uniquely demonstrated.

[0141] It is contemplated that any specific embodiment of the method, formulation, composition, or article described herein can be implemented with respect to any other method, formulation, composition, or article described herein. The methods described herein may include additional steps or may exclude one or more steps, and these steps may be performed in any order.

[0142] When providing a numerical range, it is understood that each intermediate value between the upper and lower limits of the range and any other specified value or intermediate value in the specified range is included in the present invention. The upper and lower limits of these smaller ranges may be independently included in the smaller range and are also included in the present invention, subject to any explicitly excluded limits in the specified range. If the specified range includes one or two limits, ranges that do not include either or both of these included limits are also included in the present invention.

[0143] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. All publications mentioned herein are incorporated by reference for the purpose of describing and disclosing devices, formulations and methods that may be used in conjunction with the invention described herein.

[0144] Although the present invention is susceptible to various modifications and alternative forms, specific embodiments thereof have been shown by way of example in the accompanying drawings and described in detail herein. However, it should be understood that the description of specific embodiments herein is not intended to limit the present invention to the particular forms disclosed. On the contrary, it should be recognized that many equivalents, alternatives, variations and modifications are possible, in addition to those explicitly stated, and fall within the spirit and scope of the present invention as defined by the appended claims.

[0145] References

[0146] All references listed in this application are incorporated herein by reference in their entirety for all purposes, as long as they do not conflict with the present invention. Although specific embodiments and embodiments of the disclosed subject matter have been discussed herein, these embodiments are exemplary and non-restrictive. After reviewing this specification and the following claims, many variations will become apparent to those skilled in the art.

[0147] 1. "Addressing the Pain of Corneal Neuropathy". American Academy of Ophthalmology. July 2010. Retrieved 2018-04-16.

[0148] 2. Rosenthal, Perry; Borsook, David (2016). "Ocular neuropathic pain". British Journal of Ophthalmology. 100(1): 128–134.

[0149] 3. Kalangara, Jerry P.; Galor, Anat; Levitt, Roy C.; Felix, Elizabeth R.; Alegret, Ramon; Sarantopoulos, Constantine D. (2015). "Burning Eye Syndrome: Do Neuropathic Pain Mechanisms Underlie Chronic Dry Eye?". Pain Medicine. Pages 746–755.

[0150] 4. "Neuropathic dry eye: When serum defeats tears". Ophthalmology Times. Retrieved 2018-05-02.

[0151] 5. Meng ID, Barton ST, Mecum NE, Kurose M. Corneal sensitivity following lacrimal gland excision in the rat. Invest Ophthalmol Vis Sci. 2015; 56: 3347–3354.

[0152] 6. Daou I, Beaudry H, Ase AR, Wieskopf JS, Ribeiro-da-Silva A, Mogil JS, Séguéla P. Optogenetic Silencing of Nav1.8-Positive Afferents Alleviates Inflammatory and Neuropathic Pain. eNeuro. March 16, 2016; 3(1): ENEURO.0140-15.2016.

[0153] 7. Joshi SK, Honore P, Hernandez G, Schmidt R, Gomtsyan A, Scanio M, Kort M, Jarvis MF. Additive antinociceptive effects of the selective Nav1.8 blocker A-803467 and selective TRPV1 antagonists in rat inflammatory and neuropathic pain models. J Pain. March 2009; 10(3): 306-15.

[0154] 8. Mecum NE, Russell R, Lee J, Sullivan C, Meng ID. Optogenetic Inhibition of Nav1.8 Expressing Corneal Afferents Reduces Persistent Dry Eye Pain. Invest Ophthalmol Vis Sci. November 1, 2021; 62(14): 15.

[0155] 9. Price TJ, Patwardhan A, Akopian AN, Hargreaves KM, Flores CM. Modulation of trigeminal sensory neuron activity by the dual cannabinoid-vanilloid agonists anandamide, N-arachidonoyl-dopamine and arachidonyl-2-chloroethylamide. Br. J. Pharmacol. 2004; 141: 1118–1130.

[0156] 10.BirdEV,Christmas CR,LoescherAR Assessment,Correlation ofNav1.8and Nav1.9sodium channel expression with neuropathic pain in human subjects with lingual nerve neuromas.Mol Pain.2013Oct 21,9:52.

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[0158] 12.Rosenthal P,Borsook D.Ocularneuropathic pain.Br J. Ocular neuropathic pain Ophthalmol.2016January100(1):128-34.doi:10.1136 / bjophthalmol-2014-306280.Epub2015January5.PMID:25943558;PMCID:PMC4717373.

[0159] 13.Ebrahimiadib N,Yousefshahi F,Abdi P,Ghahari M,ModjtahediBS.OcularNeuropathic Pain:An Overview Focusing on Ocular Surface Pains.ClinOphthalmol.20209 / 25 / 14:2843-2854.doi:10.2147 / OPTH.S262060.PMID:33061269;PMCID:PMC7524198.

[0160] 14.Galor A,Levitt RC,Felix ER,Martin ER,Sarantopoulos CD.Neuropathicocular pain:an importantyet underevaluated feature ofdryness eye.Eye(London).2015May3:29(3):301-12.Doi:10.1038 / eye.2014.263.Epub2014May117.PMID:25376119;PMCID:PMC4366454.

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Claims

1. Use of a preparation for treating nociceptive eye pain and / or neuropathic eye pain in a subject, comprising: topically administering to the ocular surface of a subject suffering from nociceptive ocular pain and / or neuropathic ocular pain an effective amount of a formulation comprising a selective Nav1.8 inhibitor, wherein the Nav1.8 inhibitor is a peripheral nerve desensitizer, and The Nav1.8 inhibitor is ambroxol and / or an ambroxol derivative.

2. The use according to claim 1, wherein administration of the formulation provides partial preservation of sensation in the eye.

3. The use according to claim 2, wherein the partial preservation of sensation in the eye comprises preservation of at least 10% of corneal sensation.

4. The use according to claim 2, wherein the partial preservation of sensation in the eye comprises preservation of at least 20% of corneal sensation.

5. The use according to any one of claims 1 to 4, wherein the weight percentage of the ambroxol and / or the ambroxol derivative is 0.001% to 10% based on the total weight or total volume of the preparation.

6. The use according to any one of claims 1 to 5, wherein the weight percentage of the ambroxol and / or the ambroxol derivative is 0.05% to 2.0% based on the total weight or total volume of the preparation.

7. The use according to any one of claims 1 to 6, wherein the preparation further comprises cyclodextrin.

8. The use according to any one of claims 1 to 7, wherein the administration of the preparation is associated with ocular trauma or ophthalmic surgery.

9. The use according to any one of claims 1 to 8, further comprising administering an analgesic.

10. The use according to claim 9, wherein the formulation is topically applied to the ocular surface prior to administration of the analgesic.

11. The use according to claim 9, wherein the formulation is topically administered at about the same time as the analgesic is administered.

12. The use according to claim 9, wherein the formulation is topically administered after administration of the analgesic.

13. The use according to any one of claims 9 to 12, wherein the preparation is topically administered before the onset of postoperative pain or ocular trauma pain, wherein the onset of postoperative pain or ocular trauma pain has been delayed by the administration of analgesics.

14. The use according to any one of claims 9 to 13, wherein the preparation continues to treat nociceptive and neuropathic ocular pain after the effect of the analgesic is no longer effective.

15. The use according to any one of claims 9 to 15, wherein the analgesic comprises tetracaine, proparacaine, chloroprocaine, lidocaine or bupivacaine.

16. The use according to any one of claims 9 to 15, wherein the analgesic comprises an opioid.

17. The use according to any one of claims 9 to 15, wherein the analgesic comprises a non-steroidal anti-inflammatory drug.

18. The use according to any one of claims 1 to 17, wherein the formulation is administered within 60 minutes of a subject undergoing ocular trauma or ophthalmic surgery.

19. The use according to any one of claims 1 to 17, wherein the formulation is administered within 20 minutes of a subject undergoing an ocular injury or ophthalmic surgery.

20. The use according to any one of claims 1 to 17, wherein the formulation is administered within 5 minutes of a subject undergoing an ocular injury or ophthalmic surgery.

21. The use according to any one of claims 1 to 20, wherein a device provides for administration of the formulation.

22. The use according to any one of claims 1 to 21, wherein the formulation comprises a biocompatible polymer.

23. The use according to claim 22, wherein the ambroxol and / or the chemical derivative of ambroxol is impregnated in the biocompatible polymer.

24. Use according to claim 22 or 23, wherein the biocompatible polymer is dissolved in a carrier.

25. The use according to any one of claims 22 to 24, wherein the biocompatible polymer comprises poly (2-hydroxyethyl methacrylate) (p-HEMA hydrogel), poly (lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), hydroxypropyl cellulose, anecortave acetate (AnA), gelatin and / or collagen.

26. The use according to any one of claims 1 to 25, wherein the formulation further comprises an additive, wherein the additive is a demulcent, a preservative, an emollient or a pH adjuster.

27. The use according to any one of claims 1 to 26, wherein administration of an effective amount of the formulation results in a reduction in subjective symptoms or an improvement in a quality of life measure.

28. Use of the formulation of claim 1 in the preparation of a medicament for treating nociceptive ocular pain and / or neuropathic ocular pain in a subject, wherein the treatment comprises administering an effective amount of the formulation to the surface of the eye of the subject.

29. A formulation for use according to claim 1, comprising a composition comprising: Based on the total weight or volume of the preparation, 0.01% to 10% by weight of ambroxol and / or ambroxol derivatives; and cyclodextrin.

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