Treating pain associated with diabetic peripheral neuropathy

Abstract

The invention features methods of preventing and / or treating neuropathic pain associated with diabetic peripheral neuropathy (DPN).

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 192,248, filed May 24, 2021, the entire contents of which are incorporated herein by reference for all purposes. Technical Field

[0002] The present invention relates to compounds and their use in the treatment of neuropathic pain associated with diabetic peripheral neuropathy (DPN). Background Art

[0003] Neuropathy is a disease or abnormality of the nervous system that afflicts more than 20 million Americans. In fact, recent studies have observed that neuropathic pain affects approximately 1 in 10 adults, and the economic burden of treating this pain is increasing.

[0004] Neuropathy is relevant to the development of neuropathic pain.Neuropathic pain can occur due to damage to the peripheral or central nervous system.Peripheral neuropathic pain is caused by damage to nerve structures (such as peripheral nerve endings or nociceptors), which become extremely sensitive to stimulation and can produce impulses in the absence of stimulation.Injury can occur due to many reasons, such as diseases such as diabetes (i.e. DPN), chemotherapy treatments and advanced cancers, viruses (e.g., herpes zoster or HIV) and physical injuries (e.g., accidents or surgical operations).

[0005] Peripheral nerve damage can lead to a pathological state characterized by the presence of persistent spontaneous pain that is often associated with hyperalgesia (an increased response to noxious stimuli) and allodynia (pain caused by non-painful stimuli). Hyperalgesia and allodynia are associated with central sensitization, in which CNS nociceptive neurons exhibit increased excitability due to a lowered threshold for stimulation triggered by persistent input or peripheral injury. Central sensitization has been implicated in the generation and maintenance of neuropathic pain associated with peripheral neuropathy.

[0006] From a symptom perspective, peripheral neuropathy can cause sharp pain, dull pain, painful burning or cold sensations, paresthesias, loss of proprioception, numbness, or even loss of pain sensation.

[0007] There is a worldwide need for additional pain therapies, and neuropathic pain has become a major health problem for a large population.

[0008] Neuropathic pain is often treated with so-called unconventional analgesics (such as antidepressants like duloxetine and amitriptyline, or antiepileptic drugs like gabapentin or pregabalin). In addition, local anesthetics, including lidocaine, have been used to treat and control neuropathic pain. Despite evidence to the contrary, nonsteroidal anti-inflammatory drugs (NSAIDs) are still widely used to control neuropathic pain. However, according to a recent review of clinical trials, there is no evidence that NSAIDs significantly reduce pain in patients with neuropathic pain (Moore et al. Cochrane Database of Systematic Reviews (2015); 10:1–25), nor have clinical results shown a statistically significant difference between NSAIDs and placebo. The Cochrane Library concluded that NSAIDs should not be recommended for the treatment of neuropathic pain.

[0009] DPN is the peripheral nerve damage caused by diabetes, and represents one of the most serious complications of the disease. About half of all diabetic patients have some form of nerve damage, and hyperglycemia is the main cause of peripheral neuropathy in DPN. DPN can affect both small and large nerves, which protect the human body by sending signals about pain and temperature changes to the brain, and detect touch, pressure and help maintain balance. Clinical guidelines recommend that pain in painful diabetic neuropathy be relieved by using antidepressants (such as duloxetine) and / or antiepileptic drugs (such as gabapentin and pregabalin) as well as opioids and topical agents (such as capsaicin). The therapeutic efficacy currently used for the pain associated with DPN is limited, and significant side effects may be caused.

[0010] Therefore, there is a strong need for compounds that treat and / or prevent pain associated with peripheral neuropathies, in particular DPN. Summary of the Invention

[0011] The present inventors have unexpectedly discovered that sulindac phosphate (PS) is effective in treating and preventing pain associated with DPN.

[0012] PS is a nonsteroidal compound with anti-inflammatory activity. However, unlike its parent compound, the NSAID sulindac, PS does not inhibit COX-1 and COX-2 expression and is therefore not a typical NSAID. PS has previously been shown to have anti-cancer and anti-inflammatory properties through its inhibition of NF-κB activation and changes in the MAP K signaling branch, as well as activity in treating rheumatoid arthritis in inflammatory mouse models by inhibiting key pro-inflammatory signaling pathways (Mackenzie et al. (2010) Gastroenterology 139(4):1320–32 and Mattheolabakis et al. (2013) Pharm Res 30(6):1471–82). WO 2019 / 067919 showed that PS has anti-inflammatory activity in an acute model of dry eye disease (DED). Furthermore, in this model, PS was observed to restore the suppressed ocular sensitivity in DED, suggesting that the effect of PS is to increase rather than decrease nociception. Although PS is not a typical NSAID, as described above, it exhibits NSAID-like activity when administered to normal eyes in a DED model. However, these observations fail to demonstrate a role for PS in the treatment of neuropathic pain associated with DPN. Furthermore, clinical guidelines in the field recommend avoiding the use of NSAIDs for the treatment of all types of neuropathic pain, and therefore, anti-inflammatory activity alone is considered insufficient for treatment.

[0013] However, the present inventors have considered the activity of PS in specific animal models of neuropathic pain and demonstrated unexpected therapeutic efficacy, comparable to that of direct-acting nerve-blocking anesthetics such as lidocaine and pregabalin. Specific animal models are important in the development of therapies for treating neuropathic pain. Indeed, given the pathogenesis of pain associated with peripheral neuropathy, the observed efficacy of a specific compound in an alternative pain model does not necessarily indicate the compound's effectiveness in treating neuropathic pain. Consistent with this, even if the clinical syndrome is similar, it is not possible to extrapolate the use of effective drugs from other forms of neuropathic pain to the neuropathic pain of particular interest. For example, gabapentin has shown different efficacy in treating different forms of neuropathic pain. Therefore, the animal model used in early testing prior to further clinical development is crucial. Based on a specific animal model of DPN neuropathic pain, the observations herein demonstrate that PS has unprecedented efficacy in treating and / or preventing neuropathic pain associated with DPN.

[0014] Therefore, in a first aspect, the present invention provides a method for treating and / or preventing neuropathic pain associated with DPN, the method comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that neuropathic pain associated with DPN is treated and / or prevented.

[0015] In some embodiments, PS is a sulfoxide form of PS. Thus, PS may have Formula I (PS-I):

[0016]

[0017] In other embodiments, PS is a sulfide form of PS. Thus, PS may have Formula II (PS-II):

[0018]

[0019] Herein, reference to "sulindac phosphate" or "PS" encompasses both PS-I and PS-II. The sulfide form of the compound is preferred. Compounds of Formula I and II are described in U.S. Patent No. 8,236,820, which is hereby incorporated by reference in its entirety.

[0020] As mentioned above, the nerve damage associated with DPN can lead to excessive activation of the pain signaling pathway, thereby causing peripheral neurons and / or central neurons to be sensitive, and the neurons show a reduced stimulation threshold. Therefore, subjects with DPN may experience pain due to this sensitization, for example, experiencing pain caused by non-painful stimuli (allodynia) or experiencing pain (hyperalgesia) in response to an aggravation of noxious stimuli. Based on the observations herein, PS can have a direct analgesic effect, for example, by reducing the neuronal signaling involved in pain sensation. In addition, PS can alleviate the pain produced by peripheral sensitization or by central sensitization. Therefore, PS can reduce or prevent the pain signaling that occurs in the center. PS can reduce or prevent the pain signaling that occurs in the sciatic nerve. PS can reduce or prevent the pain signaling that occurs in the dorsal root ganglion. In view of the fact that PS shows that peripheral neurons are promoted to the spinal cord, PS can reduce or prevent the pain signaling that occurs in the spinal cord. In some embodiments, neuropathic pain is allodynia. Allodynia can be a reaction to mechanical stimulation and / or thermal stimulation. In addition, in some embodiments, neuropathic pain is hyperalgesia.

[0021] PS can be formulated into pharmaceutical compositions for use in the present invention. In some embodiments, the pharmaceutical composition comprises PS and one or more pharmaceutically acceptable excipients. PS can be formulated for topical administration, particularly topical administration to the upper and lower extremities of a subject (i.e., overstocking and glove distribution). BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 – Schematic overview of neuropathic pain relevant to DPN treatment studies. STZ is streptozotocin. PWT is paw withdrawal threshold test.

[0023] Figure 2 – Effects of PS compared with vehicle on neuropathic pain associated with STZ-induced DPN.

[0024] Figure 3 – Effects of sulindac, lidocaine, and pregabalin on neuropathic pain associated with DPN.

[0025] Figure 4 – Schematic overview of neuropathic pain associated with DPN prevention studies. STZ is streptozotocin. PWT is paw withdrawal threshold test.

[0026] Figure 5 - Effect of PS on the prevention of neuropathic pain associated with DPN. *, p<0.0001 (STZ vs. naive); **, p<0.004 (PS vs. vehicle); ***, p<0.001 (lidocaine vs. vehicle).

[0027] Figure 6 – Schematic outline of PS metabolism.

[0028] Figure 7 - Biodistribution of PS in different tissues after topical application. SN = sciatic nerve. DRG = dorsal root ganglion.

[0029] Figure 8 – Biodistribution of PS metabolites in different tissues after topical administration of PS. SN = sciatic nerve. DRG = dorsal root ganglion. DETAILED DESCRIPTION

[0030] definition

[0031] The following definitions of pain types are based on those of the International Association for the Study of Pain (IASP). "Pain" is an unpleasant sensory and emotional experience associated with or similar to actual or potential tissue damage. "Neuropathic pain" is caused by a lesion or disease of the somatosensory nervous system. Neuropathic pain is a clinical description (rather than a diagnosis) that requires a lesion or disease that clearly meets established neurological diagnostic criteria. Neuropathic pain patients may experience one or more sensations described as heat, burning, throbbing, shooting, tingling, sharp, cramping, aching, tingling, numbness, or a pins-and-needles sensation. When diagnostic tests (e.g., imaging, neurophysiology, biopsy, laboratory tests) reveal abnormalities or when there is obvious trauma, the term "lesion of the somatosensory nervous system" is typically used. When the underlying cause of the lesion is known (e.g., stroke, vasculitis, diabetes, genetic abnormalities), the term "disease of the somatosensory nervous system" is typically used. "Peripheral neuropathic pain" is pain caused by a lesion or disease of the peripheral somatosensory nervous system. “Central neuropathic pain” is pain caused by a lesion or disease of the central somatosensory nervous system. “Central sensitization” refers to increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input. “Peripheral sensitization” refers to increased responsiveness and a lowered threshold of nociceptive neurons in the periphery to stimulation of their receptive fields. “Allodynia” is pain caused by stimuli that are not normally painful. “Hyperalgesia” refers to increased pain caused by stimuli that are normally painful.

[0032] Generally, the term "disease" refers to a state or condition in a patient or subject that can be treated using the methods provided herein.

[0033] The term "therapeutically effective amount" refers to an amount of a compound or combination of compounds as described herein that is sufficient to achieve the intended application, including but not limited to treating and / or preventing disease.

[0034] "Pharmaceutically acceptable excipients" are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inert ingredients contained in pharmaceutical compositions. The use of such pharmaceutically acceptable excipients for formulating active pharmaceutical ingredients is well known in the art. Unless any conventional pharmaceutically acceptable excipient is incompatible with PS, its use in the therapeutic compositions of the present invention is contemplated.

[0035] The use of the term "about" when referring to numbers is optional and means that the number referred to is an approximation within typical experimental variability (or within statistical experimental error), and therefore the number may vary accordingly.

[0036] The term "comprising" encompasses "including" as well as "consisting of, for example, a composition "comprising" X may consist only of X, or may include additional substances (eg, X+Y).

[0037] Pain associated with diabetic peripheral neuropathy

[0038] The pathology that occurs in diabetic patients, particularly hyperglycemia, can cause neuronal damage, leading to peripheral neuropathy and associated neuropathic pain. Neuropathic pain in these patients develops over time and is often more severe in patients with long-term disease, and can include tingling, burning, and / or drilling pain. In some embodiments, the present invention provides a method for preventing neuropathic pain associated with DPN, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that neuropathic pain associated with DPN is prevented. In other embodiments, the present invention provides a method for treating neuropathic pain associated with DPN, comprising administering a therapeutically effective amount of PS to a subject in need thereof, such that neuropathic pain associated with DPN is treated. As DPN develops over time in diabetic patients, subjects may experience worsening neuropathic pain over time, and therefore would benefit from analgesics that can both treat ongoing neuropathic pain and prevent the development of further neuropathic pain. Therefore, in some embodiments, PS can be used to treat and prevent neuropathic pain associated with DPN. According to the above, the present invention provides PS for treating and / or preventing neuropathic pain associated with DPN. In addition, the present invention provides the use of PS in the manufacture of a medicament for treating and / or preventing neuropathic pain associated with DPN.

[0039] Based on the observations herein, PS has a direct analgesic effect on neuropathic pain associated with DPN. Neuropathic pain associated with DPN can be tingling, burning pain and / or drilling pain. Subjects with DPN may experience persistent and symmetrical neuropathic pain in the lower and upper limbs. When treating neuropathic pain associated with DPN, PS can alleviate or eliminate neuropathic pain. When treating neuropathic pain associated with DPN, PS can also reduce or eliminate one or more sensory symptoms associated with DPN. When preventing neuropathic pain associated with DPN, PS can reduce the incidence of neuropathic pain. When preventing neuropathic pain associated with DPN, PS can also reduce the incidence of one or more sensory symptoms associated with DPN.

[0040] The sensory symptoms of DPN include paresthesia (e.g., numbness, tingling, tingling, or forking), burning or shooting sensations (i.e., electric shock-like). DPN typically affects the extremities such as the feet, hands, legs, and arms, where the nerve fibers are the longest and most numerous, and patients typically have a "stocking and glove" distribution. Even if the sensory symptoms experienced by a subject with DPN are not considered painful (or do not reach the threshold necessary to be considered pain per se), PS can be used to alleviate, eliminate, or reduce the incidence of one or more sensory symptoms experienced by a subject with DPN (including those listed above). PS can be used to reduce, eliminate, or reduce the incidence of stocking and glove distribution in a subject with DPN.

[0041] As described above, the neuropathic pain associated with DPN may be the result of central sensitization, resulting in allodynia and / or hyperalgesia. PS can reduce, eliminate or reduce the incidence of neuronal signaling involved in the pain sensation in subjects with DPN. PS can reduce, eliminate or reduce the incidence of pain produced by peripheral sensitization or by central sensitization. Therefore, PS can reduce, eliminate or reduce the incidence of pain signaling occurring in the center. PS can reduce, eliminate or reduce the incidence of pain signaling occurring in the sciatic nerve. PS can reduce, eliminate or reduce the incidence of pain signaling occurring in the dorsal root ganglion. In view of the fact that PS shows that peripheral neurons are promoted to the spinal cord, PS can reduce, eliminate or reduce the incidence of pain signaling occurring in the spinal cord. The neuropathic pain in subjects with DPN can be allodynia (e.g., mechanical or thermal allodynia). Additionally or alternatively, the neuropathic pain in subjects with DPN can be hyperalgesia.

[0042] Neuropathic pain in patients with DPN can be measured according to a visual analog pain scale or using any other appropriate method known in the art.

[0043] Pharmaceutical composition

[0044] The PS used in the methods of the present invention can be formulated into a suitable pharmaceutical composition for administration to a subject suffering from DPN. The pharmaceutical composition is generally formulated to provide a therapeutically effective amount of the PS and may further comprise a pharmaceutically acceptable excipient.

[0045] Neuropathic pain associated with DPN can occur in various locations on the body. However, as outlined above, DPN tends to affect peripheral nerves in the upper and lower extremities, and therefore the extremities, explaining the "stocking and glove" distribution experienced by these patients. Therefore, particularly useful pharmaceutical compositions comprising PS are those that can be applied directly to peripheral sites experiencing neuropathic pain, such as the upper and lower extremities of a subject. In addition, pharmaceutical compositions comprising PS can be applied to those sites experiencing one or more sensory symptoms of DPN. Thus, pharmaceutical compositions comprising PS can be formulated for topical administration. In particular, pharmaceutical compositions comprising PS can be formulated for dermal administration, particularly for application to the skin of the upper and / or lower extremities of a subject.

[0046] In some embodiments, pharmaceutical compositions comprising PS can be formulated as semisolids or liquids. Thus, pharmaceutical compositions comprising PS can be formulated as creams, gels (e.g., hydrogels), lotions, ointments, foams, and / or sprays. These compositions vary in the relative concentrations of oil and water, resulting in compositions having different densities. Varying the density of the formulation is one way to control the exposure of the affected area to the pharmaceutical composition. For example, a formulation with a lower density needs to be rubbed in until absorbed, potentially resulting in a shorter exposure time. Alternatively, a denser formulation that is less easily absorbed can allow for extended exposure of the area to the pharmaceutical composition. One skilled in the art will appreciate the ability to formulate topical pharmaceutical compositions to alter the relative exposure of the area to the active pharmaceutical ingredient.

[0047] In other embodiments, the pharmaceutical composition comprising PS can be formulated as a patch that can be applied to the skin. The patch can be manufactured in such a way as to ensure controlled release of PS to the affected area.

[0048] Formulations suitable for topical administration and appropriate pharmaceutically acceptable excipients are well known in the art. Exemplary formulations for topical administration are provided in WO 2019 / 067919, which is hereby incorporated by reference in its entirety.

[0049] In some embodiments, PS formulations suitable for topical administration may comprise PS at a concentration of about 0.5% w / w to about 15% w / w of the pharmaceutical composition. Thus, the concentration of PS may be 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11%, 10.5%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5% w / w of the pharmaceutical composition. As an illustrative example, when formulated as a topical cream, the concentration of PS may be less than or equal to 8% w / w of the pharmaceutical composition, for example, about 5% w / w of the pharmaceutical composition, and particularly about 3% w / w of the pharmaceutical composition. As a further illustrative example, when formulated as a gel, the concentration of PS may be less than or equal to 8% w / w of the pharmaceutical composition, such as less than or equal to 5% w / w of the pharmaceutical composition, particularly less than or equal to 3% w / w of the pharmaceutical composition, such as about 2% or about 1% w / w of the pharmaceutical composition. In certain formulations, such as when formulated as a hydrogel or ointment, the concentration of PS may be 5% w / w of the pharmaceutical composition.

[0050] A single application to both hands (i.e., gloves) may require less than about 5 ml of the pharmaceutical composition, for example, about 3 ml of the pharmaceutical composition (i.e., about 1.5 ml of the pharmaceutical composition per hand). A single application to both feet (i.e., stockings) may require less than about 6 ml of the pharmaceutical composition, for example, about 4 ml of the pharmaceutical composition (i.e., about 2 ml of the pharmaceutical composition per foot).

[0051] The pharmaceutical composition comprising PS may alternatively be formulated for any other form of administration suitable for treating and / or preventing neuropathic pain associated with DPN. For example, the composition may be formulated for transdermal administration or injection, such as subcutaneous injection.

[0052] Dosage regimen

[0053] The appropriate dosage regimen of PS for the treatment and / or prevention of DPN will depend on variables such as the type and degree of pain progression (e.g., as determined according to the World Health Organization's "Pain Ladder" guidelines), the severity of the pain (e.g., acute, subacute, or chronic), the age, weight, and general condition of the particular patient, the formulation of the excipient, the route of administration, and the judgment of the attending clinician.

[0054] For topical administration, PS can be applied to cover one or more affected areas, such as the upper and lower extremities of a subject. In some embodiments, about 0.01 to about 5 g of PS can be applied to the affected area. Regarding the size of the affected area, about 0.005–0.25 g / 10 cm can be used. 2Therefore, about 0.005 g / 10 cm can be used to apply PS to the affected area. 2 , 0.01g / 10cm 2 , 0.05g / 10cm 2 , 0.1g / 10cm 2 , 0.15g / 10cm 2 , 0.2g / 10cm 2 or 0.25g / 10cm 2 Apply PS to the affected area.

[0055] In some cases, the PS may be applied for topical application and then removed from the affected area (e.g., by washing it off) before reapplication. In some cases, the PS is washed off after a period of time. Alternatively, because the analgesic effect may diminish over time and may require reapplication, in some cases, the PS is not washed off, but rather simply reapplied to the affected area after an appropriate administration period. For example, the PS may be applied to the affected area and left on the affected area (before removal or reapplication) for between about 0.5 and about 5 hours. Thus, the PS may be applied topically and left on the affected area (before removal or reapplication) for about 0.5, about 1, about 2, about 3, about 4, or about 5 hours.

[0056] Because the neuropathic pain associated with DPN is chronic, repeated topical administration of PS is necessary. Therefore, PS may be applied topically one to four times daily. Thus, PS may be applied once daily, twice daily, three times daily, or four times daily. For certain PS formulations, such as hydrogels or ointments with a PS concentration of approximately 5% w / w of the pharmaceutical composition, the formulation may be applied topically three times daily. In more severe cases, further applications of PS may be administered approximately 0.5 hours after each application.

[0057] PS can have a long-lasting analgesic effect and, therefore, can be administered less frequently. For example, PS can be applied topically less than daily, for example, every other day. In fact, for those patients who experience long-term analgesia with a single administration, PS can be applied topically less than weekly, for example, every two weeks.

[0058] For topical application of some pharmaceutical compositions, it is useful to cover the affected area with a dressing (e.g., plastic wrap or a film) after application of the pharmaceutical composition, for example, to ensure that the appropriate amount of composition is applied for an appropriate period of time. Thus, after topical application of the PS, the affected area may be bandaged.

[0059] In some embodiments, the PS can be topically administered in the form of a patch (e.g., a plaster). The use of a patch can allow for a reduction in dosing intervals and / or dosing frequency, for example, because the patch ensures controlled release of the PS. Thus, the patch can be applied to the affected area once a day, less than twice a day, less than three times a day, or less than four times a day.

[0060] PS can be administered continuously for as long as necessary. For example, PS can be administered for more than 1, 2, 3, 4, 5, 6, 7, 14, 28, 56, or 84 days. As described above, PS can be administered continuously over a long period of time to treat chronic effects, for example, for at least 3 months. Thus, in some cases, continuous dosing is achieved and maintained for as long as necessary. PS can be administered intermittently based on recurrence of neuropathic pain and / or associated sensory symptoms.

[0061] PS can be used to treat and / or prevent DPN in mammals. For example, the subject can be a human.

[0062] As described above, PS can be formulated into a suitable pharmaceutical composition for administration to a subject suffering from DPN. Thus, PS can be administered in the form of a suitable pharmaceutical composition according to the above-described dosing regimen.

[0063] Those skilled in the art will appreciate that, in certain embodiments, the dosage of such compounds may be adjusted based on the mammal being treated. For example, treatment of rats is described herein, and such dosages may or may not be modified when administering PS to humans. However, if necessary, those skilled in the art can convert the dosages provided herein as described in Guidance for Industry: Estimating the Maximum Safe Starting Dose of Therapeutic Agents in Initial Clinical Trials in Adult Healthy Volunteers, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), July 2005. The human equivalent dose (HED) can be determined based on the animal dose, which can be multiplied by the following conversion factors to provide units in mg / kg: mouse = 0.08, hamster = 0.13, rat = 0.16, ferret = 0.19, guinea pig = 0.22, rabbit = 0.32, dog = 0.54, monkey = 0.32, marmoset = 0.16, squirrel monkey = 0.19, baboon = 0.54, minipig = 0.73, minipig = 0.95.

[0064] Pharmaceutically acceptable forms of PS

[0065] Pharmaceutical compositions comprising PS may contain PS in a pharmaceutically acceptable form. The pharmaceutically acceptable form may be a solvate, derivative, and / or prodrug.

[0066] Solvates

[0067] As used herein, the term "solvate" refers to a compound that further comprises a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. In the case where the solvent is water, the solvate is a hydrate. Pharmaceutically acceptable forms of PS may include solvates of PS, such as solvates of PS-I and / or PS-II. In some embodiments, the solvate comprises at least one solvent molecule. In some embodiments, the solvate comprises less than one solvent molecule. In some embodiments, the solvate is a hydrate.

[0068] isotope

[0069] Pharmaceutically acceptable forms of PS may include isotopically labeled derivatives of PS-I. Pharmaceutically acceptable forms of PS may include isotopically labeled derivatives of PS-II. Isotopically labeled derivatives are compounds identical to PS except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. In some embodiments, the isotopically labeled derivatives of PS include one or more isotopes of hydrogen, carbon, oxygen, phosphorus, and fluorine. In some embodiments, the isotopically labeled derivatives of PS include, respectively 2 H. 3 H. 13 C. 14 C. 18 O. 17 O. 31 P. 32 P. 35 S and 18 One or more isotopes of F. In some embodiments, the isotope-labeled PS derivative comprises 2 One or more isotopes of H (e.g., deuterium). In some embodiments, the isotope-labeled PS derivative comprises 3 One or more isotopes of H (e.g., tritium). In some embodiments, the isotope-labeled PS derivative comprises 14 One or more isotopes of C.

[0070] Derivatives and prodrugs

[0071] Pharmaceutically acceptable forms of PS may include derivatives of PS-I. Pharmaceutically acceptable forms of PS may include derivatives of PS-II. In some embodiments, the derivative of PS (e.g., PS-I or PS-II) is a metabolite. In other embodiments, the pharmaceutically acceptable form of PS is a prodrug of PS, such as a prodrug of PS-I or a prodrug of PS-II.

[0072] The sulfone group can be represented structurally as: RS(=O)2-R'. In some embodiments, the derivative of PS is a sulfoxide form of PS.

[0073] PS contains an organophosphate functional group. The organophosphate functional group can be structurally represented as O=P(OR)3, O=P(OR)2(OR'), or O=P(OR)(OR')(OR"). For example, if R=CH2CH3 and R'=the rest of the molecule is PS according to Formula I or II (e.g., PS-I, PS-II, or a derivative thereof), then O=P(OR)2(OR') can represent PS.

[0074] In some embodiments, the derivative of PS is PS wherein one of the ethoxy (e.g., -OCH2CH3) groups is an OH group, or a pharmaceutically acceptable salt thereof. In some embodiments, the derivative of PS is PS wherein both ethoxy (e.g., -OCH2CH3) groups are OH groups, or a pharmaceutically acceptable salt thereof.

[0075] The activities of PS demonstrated herein will be shared by its pharmaceutically acceptable forms. Accordingly, the present invention provides pharmaceutically acceptable forms of PS for use in the methods of the present invention.

[0076] While preferred embodiments of the invention are shown and described herein, such embodiments are provided by way of example only and are not intended to otherwise limit the scope of the invention. Various alternatives to the described embodiments of the invention may be used to practice the invention.

[0077] Example

[0078] The embodiments encompassed herein will now be described with reference to the following examples. These examples are provided for illustrative purposes only, and the disclosure encompassed herein should in no way be construed as being limited to these examples, but rather should be construed to encompass any and all variations that become apparent as a result of the teachings provided herein.

[0079] Example 1 :Effects of PS in DPN rat model

[0080] DPN is induced in rats by chemically induced hyperglycemia using streptozotocin (STZ). This is a well-established model of DPN (see Morrow, Current Protocols in Neuroscience (2004); 29(1): 1–11), in which STZ (an antibiotic extract from Streptomyces acromogenes) selectively damages pancreatic beta cells. As demonstrated, PS is an effective treatment for DPN, where treatment begins after neuropathy is established.

[0081] method

[0082] Sprague-Dawley rats were fasted for 4-6 hours and then injected intraperitoneally with 45 mg / kg STZ. This procedure was performed on all experimental groups except the naive group. To prevent hypoglycemic mortality, rats received 10% sucrose water as their sole water source for the first 48 hours after injection. To ensure that only rats considered diabetic (i.e., non-fasting blood glucose levels >250 mg / dL) were included in the study, blood glucose was measured 72 hours after STZ injection.

[0083] Four weeks after STZ injection, rats were randomly divided into treatment groups, e.g. Figure 3 As shown. This delay between STZ injection and treatment allowed the establishment of chronic pain associated with peripheral and central sensitization (allodynia). Starting from the 4th week after STZ injection, PS (as 8% hydrogel) or vehicle control was topically applied to both hind paws of rats 3 times a day for 3 weeks. 0.7% sulindac hydrogel was applied 3 times a day for 1 week - this is the highest safe sulindac concentration for these animals. 5% lidocaine cream (positive control) was applied only once to both hind paws of rats 30 minutes before measuring PWT. Finally, an additional positive control, pregabalin (10 mg / kg) or its vehicle was administered orally only once, one hour before measuring PWT.

[0084] The rats were divided into 8 study groups with an average body weight of approximately 225 g in the experimental groups (1-4) and an average body weight of approximately 335 g in the control groups (5-8), as follows:

[0085] 1. Group 1: Rats undergoing the experiment for the first time (n=5)

[0086] 2. Group 2: STZ only (n=6)

[0087] 3. Group 3: STZ plus vehicle (n=6)

[0088] 4. Group 4: STZ plus PS (8% hydrogel) (n=7)

[0089] 5. Group 5: STZ plus oral vehicle (n=8)

[0090] 6. Group 6: STZ plus 0.7% sulindac hydrogel (n=7)

[0091] 7. Group 7: STZ plus 5% lidocaine cream (n=8)

[0092] 8. Group 8: STZ plus pregabalin (10 mg / kg) (n=7)

[0093] To determine the outcome of treatment, mechanical allodynia was measured using the well-established von Frey filament method. In particular, a simplified up-down method for estimating the paw withdrawal threshold (PWT) using von Frey filaments was used (as described in Bonin et al., Molecular Pain (2014); 10(26): 1–10). The results of the PWT test are expressed as the force applied (gm). Depending on the administration schedule, PWT tests were performed at weeks 4, 5, and 7, with the first measurement being the baseline (i.e., demonstrating the efficacy of STZ in establishing DPN). Measurements at weeks 5 and 7 were performed 30 minutes after the last treatment with sulindac or PS, respectively. For completeness, the difference in mean body weight of rats in the experimental and control groups did not affect the ability to compare the results from these groups (i.e., the rats were simply obtained from different batches and responded to the experimental procedures in the same way).

[0094] Figure 1 Provide a summary of the research described.

[0095] result

[0096] like Figure 2 As shown in Table 1, administration of STZ resulted in a significant decrease in PWT 4 weeks after administration (p < 0.02 compared to naive rats). Thus, as expected, the model establishes pain associated with DPN. Additional administration of vehicle had no significant effect on PWT compared to STZ alone, with the decrease in PWT relative to naive rats being similar to that of STZ alone. However, administration of PS achieved a significant increase in PWT compared to vehicle and STZ (p < 0.04 and p < 0.01, respectively), returning PWT to the threshold observed in naive rats (p < 0.01). The results are provided in Table 1. Figure 2 The corresponding value.

[0097] Table 1 - PWT in the first four study groups

[0098]

[0099] In addition, if Figure 3 As shown in Table 2, administration of vehicle or sulindac failed to inhibit the decrease in PWT induced by STZ (sulindac was not significantly different from vehicle). However, both lidocaine and pregabalin achieved a significant increase in PWT compared to vehicle (p < 0.03 and p < 0.009, respectively). Table 2 provides the results of the STZ-induced decrease in PWT. Figure 3 The corresponding value.

[0100] Table 2 - PWT in the last four study groups

[0101]

[0102] in conclusion

[0103] In one of the most reliable animal models of diabetes, topical administration of PS effectively normalized diabetic-induced neuropathic pain. In fact, PS significantly increased PWT in rats displaying STZ-induced neuropathic pain. Therefore, PS treats neuropathic pain associated with diabetic neuropathy.

[0104] While PS is effective, surprisingly, its non-phosphorylated "parent" sulindac (a typical NSAID) failed to achieve rescue in the PWT rat model and, therefore, failed to treat pain associated with DPN. This was true even when sulindac was administered at the maximum non-toxic dose and in the same manner and formulation as PS. The positive controls, lidocaine and pregabalin, are known to have central sites of action for analgesia and, as expected, demonstrated significant relief of pain associated with DPN. Thus, the observed efficacy of topically applied PS was more similar to the centrally acting positive controls than to its closely related parent compound.

[0105] Thus, PS is mechanistically distinct from its parent NSAID and may act in a manner more similar to centrally acting agents. These observations serve to demonstrate the potential of PS in established neuropathic pain associated with DPN.

[0106] Example 2 :Effect of PS in preventing neuropathic pain in a DPN rat model

[0107] DPN is induced by chemically induced hyperglycemia in rats using streptozotocin (STZ). To establish a preventive model, STZ was administered (day 0) after treatment with PS (sulindac or vehicle) starting on day -2. PS, unlike sulindac, has been shown to be effective in preventing neuropathic pain associated with DPN.

[0108] method

[0109] The animal model corresponds to that used in Example 1, but with a preventive regimen. As in Example 1, the outcome measure for determining the effect of treatment on the prevention of mechanical allodynia was the PWT test using von Frey filaments. Measurements were performed on day -3, before treatment or induction of neuropathic pain associated with DPN, and again at the end of the study period (day 28).

[0110] Rats were randomly divided into the following treatment groups, with the average body weight of all treatment groups being approximately 225 g.

[0111] 1. Group 1: Rats undergoing the experiment for the first time (n=6)

[0112] 2. Group 2: STZ only (n=8)

[0113] 3. Group 3: STZ plus vehicle (n=8)

[0114] 4. Group 4: STZ plus PS 8% (n=8)

[0115] 5. Group 5: STZ plus sulindac 0.7% (n=8)

[0116] 6. Group 6: STZ plus lidocaine cream 5% (n=8)

[0117] Each treatment group underwent a PWT assessment on day -3 to determine the baseline of mechanical allodynia. Subsequently, rats were started on a treatment regimen of PS (8% hydrogel), sulindac (0.7% hydrogel), or vehicle, depending on the treatment group, applied topically to both hind paws of the rats three times a day starting on day -2 and continuing until day 28. For those rats in the lidocaine treatment group, lidocaine cream was applied only once to both hind paws of the rats 30 minutes before the last PWT measurement on day 28. On day 0, neuropathic pain associated with DPN was induced by administering STZ, and blood glucose was checked on day 3. Four weeks after STZ administration, in order to provide sufficient time for the neuropathic pain associated with DPN (manifested as mechanical allodynia) to develop (see Figure 5 The rats were subjected to the paw withdrawal threshold test.

[0118] Figure 4 Provide a summary of the research described.

[0119] result

[0120] like Figure 5 As shown in Figure 1, using STZ causes a significant decrease in PWT after 4 weeks of use (compared with the rats that were tested for the first time, p < 0.0001). Therefore, the model has been established for the neuropathic pain associated with DPN, as also achieved in Example 1. Compared with only STZ, the additional use of vehicle does not have a significant effect on PWT. However, compared with vehicle, using PS has achieved a significant increase in PWT (p < 0.004), thereby returning PWT to the threshold value observed in the rats that were tested for the first time. The effect of PS on PWT corresponds to the effect achieved using lidocaine, and compared with vehicle, it has significantly increased PWT (p < 0.001). However, compared with vehicle, using sulindac does not have a significant effect on PWT. In fact, compared with the effect achieved using sulindac, PS has a significant effect on PWT.

[0121] Table 3 provides the Figure 5 The corresponding value.

[0122] Table 3 - PWT in the neuropathic pain prevention experiment

[0123]

[0124] in conclusion

[0125] Similar to the observations regarding the treatment experiments in Example 1, local administration of PS was effective in preventing neuropathic pain associated with DPN, as indicated by the significant increase in PWT in those rats that received prophylactic administration of PS.

[0126] In contrast to PS, sulindac (again at its maximum non-toxic dose and administered at a schedule and frequency corresponding to those used for PS) failed to prevent neuropathic pain associated with DPN. The positive control, lidocaine, known to have a central site of action for analgesia, effectively prevented neuropathic pain associated with DPN, achieving a similar normalization of PWT as achieved by PS. Thus, the observed preventive efficacy of topically applied PS is more similar to that of the centrally acting positive control than to its closely related parent compound, sulindac.

[0127] Thus, supporting the observations in Example 1, this experiment demonstrates that even in a prophylactic setting, PS is mechanistically distinct from its parent NSAID, demonstrating therapeutic efficacy similar to centrally acting lidocaine. These observations serve to demonstrate the potential of PS in preventing neuropathic pain associated with DPN.

[0128] Example 3 : Pharmacokinetics and biodistribution of PS

[0129] Given the ability of PS to treat and prevent neuropathic pain associated with DPN, particularly with efficacy comparable to centrally acting agents such as pregabalin and lidocaine, the site of action of PS has been investigated. Despite local administration, PS has been found to travel intraneurally from the periphery to the spinal cord.

[0130] method

[0131] 8% PS ointment was applied topically to each hind paw (50 μl per paw) and gently massaged. Mice (n = 4-5 mice / time point) were euthanized by CO2 inhalation at 0.5, 1, 3, 5, 12, 18, and 24 hours. Blood was drawn immediately after death. Tissues, including paw skin, paw muscle, leg muscle, sciatic nerve, and bilateral lumbar DRG, were rapidly dissected, immediately frozen in liquid nitrogen, and stored at -80°C until analysis.

[0132] As previously described (Wen et al., Int J Pharm (2019); 557: 273-279), each plasma sample was mixed with double volume of acetonitrile and centrifuged at 13,200 rpm for 15 minutes. Tissue samples were weighed, ddH2O (100-300 μL, depending on tissue weight) was added and homogenized. After adding acetonitrile (twice the volume of the homogenate), the mixture was sonicated for 10 minutes, centrifuged at 13,200 rpm for 15 minutes, and analyzed by HPLC, as reported (Wen et al., 2019). The limit of quantification for PS was 0.1 μM, and the limit of quantification for sulindac, sulindac sulfone, sulindac sulfide, and its glucuronidated derivatives was 0.05 μM.

[0133] result

[0134] PS can be rapidly metabolized into multiple metabolites in vitro and in vivo, including PS sulfide, PS sulfone, sulindac, sulindac sulfide and sulindac sulfone ( Figure 6 Glucuronide of sulindac, which is primarily formed in the liver, and its metabolites have also been identified. Because the metabolism and PK / biodistribution of PS vary depending on its route of administration, we performed studies in normal mice in which PS was topically administered into the hind paw, with a particular focus on the sciatic nerve and dorsal root ganglion (DRG), which are affected in DPN.

[0135] like Figure 7 PS was detected in the paw skin, its application site, subcutaneous muscle, leg muscle, sciatic nerve, and DRG as shown in Table 4. As expected (Xie et al., Br J Pharmacol (2012a); 165:2152-2166), PS was not detected in the systemic circulation.

[0136] PS concentration decreases gradually from the skin to the most distant DRG, starting from C max (from 194.7±5.3μM to 0.3±0.1μM) and AUC 0-24h The corresponding values of PS T were confirmed (from 1,609.8 μM·h to 4.5 μM·h). max The same was observed in all tissues (0.5 h), except for DRG, which showed a prolonged T max (18 hours), which may reflect the way in which PS reaches it, as discussed below. Another interesting feature is the t 1 / 2 The differences were within a relatively narrow range (11.4-20.6 hours), compared to much more prolonged values of 57.4 hours in the sciatic nerve, and possibly even more prolonged values in the DRG, which could not be determined with reasonable precision.

[0137] These differences suggest differential metabolic capacities of PS between nerves and skin, as well as muscles.

[0138] Table 4-PK parameters of PS in mouse tissues and peripheral blood of normal mice

[0139]

[0140] *, cannot be determined. **, cannot be calculated because intact PS could not be detected. N = 4-5 mice / time point.

[0141] Only three PS metabolites were detected: sulindac, sulindac sulfone, and sulindac sulfide. Figure 8 and Table 5). No glucuronidation products were detected. Sulindac was the predominant metabolite, with sulindac sulfide and sulindac sulfone levels being <20% of sulindac levels. Sulindac levels were approximately 25% of PS levels in all tissues except the sciatic nerve (higher) and DRG (equal).

[0142] Table 5 - PK parameters of sulindac in mouse tissues and peripheral blood of normal mice

[0143]

[0144] *, cannot be determined. N = 4-5 mice / time point.

[0145] Sciatic nerve (C max =0.9±0.1μM; AUC 0-24h =12.0 μM·h) and DRG (C max =0.3±0.1μM; AUC 0-24h =4.5 μM·h) is of particular interest, as both are targets of neuropathic pain associated with DPN. max The PS levels in DRG were very high, and were lower compared with those in sciatic nerve, suggesting that PS reaches DRG by passing through the sciatic nerve from the skin.

[0146] in conclusion

[0147] These experiments demonstrate that locally applied PS can reach the key action sites (i.e., sciatic nerve and dorsal root ganglion) that are known to participate in the production of neuropathic pain associated with DPN. In addition, in view of its rapid metabolism in the bloodstream, the results demonstrate that PS reaches these action sites by passing through the central nervous system along peripheral neurons (e.g., sciatic nerve), finding significant concentrations in DRG. Therefore, without wishing to be bound by theory, these observations confirm that PS directly exerts its analgesic activity on neurons and may exert its analgesic activity in the central action site, similar to the activity of central action analgesics such as lidocaine and pregabalin. This action site reflects the equivalent efficacy of PS and pregabalin and lidocaine in treating and preventing the above-mentioned observed neuropathic pain associated with DPN.

[0148] Example 4 : Summary of observations

[0149] The observations herein demonstrate that PS has unprecedented analgesic activity in the prevention and treatment of neuropathic pain associated with DPN using a well-established animal model. Thus, the experiments described above demonstrate that PS is capable of reducing neuropathic pain signaling caused by DPN. Following topical administration, PS has been shown to follow an ascending trajectory along peripheral neurons (e.g., the sciatic nerve) toward the spinal cord and achieve significant analgesic effects on neuropathic pain associated with DPN. This topical route offers low systemic clearance, reduced drug interactions, improved patient tolerance, and ease of use in combination with oral medications.

[0150] These observations demonstrate the previously unrecognized activity and therapeutic utility of PS, a compound that belongs to the broader class of NSAIDs but does not possess all the properties of this family of compounds. In fact, in contrast to the observations for the NSAID, sulindac, the data herein demonstrate that the activity of PS is more similar to analgesics that directly target neuronal activity and have the potential to act at both peripheral and central sites. Indeed, the above results confirm that PS can alleviate pain caused by allodynia, which is known to include pain produced by peripheral and central sensitization. The model was established for four weeks before treatment randomization, clearly establishing the central sensitization evidenced by allodynia. Therefore, without wishing to be bound by theory, PS has a direct effect on neuronal pain signaling, similar to the established mechanism of action of anesthetics. Indeed, the results indicate that PS can reduce pain signaling from both peripheral and central sensitization, indicating both peripheral and central sites of action for this compound's analgesic activity. Of course, this activity differs from the established effects of PS and typical NSAIDs as anti-inflammatory agents.

[0151] Early observations on the activity of PS were limited to its anti-inflammatory activity. For example, WO 2019 / 067919 proposed a role for PS in the treatment of DED using an acute DED model, in which concanavalin A (ConA) was administered to the lacrimal glands of rabbits simultaneously with PS. In this case, the anti-inflammatory activity of PS resulted in a limited inflammatory response to ConA, thereby preventing the formation of DED. These observations confirm the anti-inflammatory activity of PS and suggest its utility in preventing the establishment and maintenance of the inflammatory component of DED. The observations in this acute DED model failed to provide any evidence that PS can act directly on nerves to reduce neural signaling caused by neuropathic pain. Any reduction in pain in this acute DED model can only be considered a result of PS inhibiting the inflammatory response (i.e., the pathology responsible for triggering the activation of pain sensors). In fact, the results of the DED model showed that PS improved corneal sensitivity, suggesting an increase in nociception, which is contrary to the expected effect for analgesics. Of course, regardless of any suggestion of analgesic activity of PS, such activity observed in an acute DED model provides no indication of corresponding activity in neuropathic pain, and certainly not in neuropathic pain associated with DPN.

[0152] The experiments herein were conducted in a specific animal model of neuropathic pain associated with DPN. As mentioned above, the use of an appropriate animal model is crucial for demonstrating the potential efficacy of a compound in a specific type of neuropathic pain. The efficacy of a drug for pain caused by peripheral neuropathy cannot be inferred from its efficacy for other forms of pain or even other forms of neuropathic pain. In fact, the pathogenesis of specific forms of neuropathic pain is different, and therefore therapeutic agents with different activities are needed to treat and / or prevent them. Therapies need to be designed based on the specific pathophysiology of neuropathic pain and tested in appropriate models. For example, DPN causes extensive nerve damage through diabetic metabolic abnormalities, including microvascular ischemia, increased activity of the polyol pathway of glucose metabolism, protein kinase C activation, lack of insulin-mediated neurotrophic effects, and alterations in the fatty acid pathway, while other neuropathies may occur due to demyelination or impaired calcium metabolism, for example due to the administration of toxic chemotherapeutic agents. Therefore, based on their specific pathophysiology, the effects on large and small fibers differ between DPN and other forms of neuropathy. The only reliable determination of the efficacy of a compound in treating neuropathic pain caused by this pathophysiology is to test the compound in an appropriate DPN neuropathic pain model, as shown above. Without these observations, there is a lack of any indication of the pain-relieving activity of PS in the context of neuropathic pain associated with DPN.

[0153] The observations herein demonstrate that the therapeutic utility of PS exceeds that proposed for typical NSAIDs. In fact, Moore et al. (Cochrane Database of Systematic Reviews (2015); 10: 1-25) outline that NSAIDs have no therapeutic efficacy in peripheral neuropathic pain. In the above experiments, the unique activity of PS compared to typical NSAIDs was confirmed by comparison with its parent compound, sulindac. Sulindac was unable to alleviate established allodynia (i.e., caused by sensitization of peripheral and central neurons), indicating that, unlike PS, sulindac does not provide a direct analgesic effect on neurons damaged in neuropathic pain caused by DPN. The lack of any response to sulindac in this model is likely due to the fact that, once allodynia pain is established, the pain is caused by neuropathic nerve damage, not by inflammation (i.e., any anti-inflammatory activity of sulindac is insufficient to prevent neuropathic pain). Therefore, the analgesic activity of PS is unique and not shared by closely related NSAIDs. Based on the observations made herein with sulindac, any so-called analgesic activity of NSAIDs observed in the prior art is a reflection of their anti-inflammatory activity (i.e., stopping the initial trigger that causes pain), rather than actual analgesic activity directed at neural signaling (i.e., resulting in a reduction in pain caused by nerve damage and hypersensitivity). In fact, if a typical NSAID (e.g., sulindac) could act directly on neurons with analgesic activity, sulindac would be expected to reduce the allodynia observed in the above models.

[0154] Thus, the present inventors have demonstrated that PS has novel and unexpected activity in the treatment and / or prevention of neuropathic pain associated with DPN. As described above, this activity exceeds the anti-inflammatory activity previously observed for PS and related NSAIDs. In fact, unlike typical NSAIDs, the observations herein demonstrate that PS has direct activity on both peripheral and central nerves, similar to the site and mechanism of action of established analgesics such as lidocaine and pregabalin. Furthermore, PS can be easily administered (e.g., topically) and has limited side effects (Mackenzie et al. (2010) Gastroenterology 139(4):1320–32), making it an improved therapy for neuropathic pain associated with DPN, even compared to these centrally acting analgesics.

[0155] It will be understood that the foregoing describes the inventor's work by way of example only and that modifications may be made while remaining within the scope and spirit of the invention.

Claims

1. Use of sulindac phosphate (PS) in the preparation of a medicament for treating and / or preventing neuropathic pain associated with diabetic peripheral neuropathy (DPN) in a subject.

2. The method of claim 1, wherein: a) treating the neuropathic pain including reducing or eliminating one or more sensory symptoms associated with DPN; and / or b) preventing said neuropathic pain comprises reducing the incidence of one or more of said sensory symptoms associated with DPN.

3. The method of claim 2, wherein the one or more sensory symptoms are selected from the group consisting of paresthesia, burning sensation, and shooting sensation.

4. The method of claim 3, wherein the paresthesia comprises one or more of numbness, tingling, prickling or forking.

5. The method of claim 1, wherein: a) PS reduces, eliminates, or reduces the incidence of neuronal signaling involved in pain perception; b) PS alleviates, eliminates or reduces the incidence of pain caused by peripheral sensitization; and / or c) PS alleviates, eliminates or reduces the incidence of pain caused by central sensitization.

6. The method of claim 1, wherein PS reduces, eliminates or lowers the incidence of pain signal transmission occurring in the central nervous system.

7. The method of claim 5, wherein PS reduces, eliminates or lowers the incidence of pain signal transduction occurring in the central nervous system.

8. The method of claim 1, wherein: a) PS reduces, eliminates or reduces the incidence of pain signaling occurring in the sciatic nerve; and / or b) PS reduces, eliminates or lowers the incidence of pain signaling occurring in the dorsal root ganglia.

9. The use of claim 1, wherein the neuropathic pain is allodynia.

10. The use according to claim 9, wherein the allodynia is mechanical allodynia and / or thermal allodynia.

11. The use according to claim 1, wherein the neuropathic pain is hyperalgesia.

12. The use of claim 1, wherein the subject is a human.

13. The method of claim 1, wherein the PS has the formula I (PS-I):

14. The method of claim 1, wherein the PS has the formula II (PS-II):

15. The use of claim 1, wherein the PS is formulated as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

16. The use of claim 15, wherein the pharmaceutical composition comprising PS is formulated for topical administration.

17. The method of claim 16, wherein: a) the pharmaceutical composition comprising PS is formulated as a semisolid; or b) The pharmaceutical composition comprising PS is formulated as a liquid.

18. The use of claim 16, wherein the pharmaceutical composition comprising PS is a lotion.

19. The use of claim 16, wherein the pharmaceutical composition comprises PS at a concentration of 0.5% to 15% w / w of the pharmaceutical composition.

20. The use of claim 19, wherein the pharmaceutical composition comprises PS at a concentration of 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11%, 10.5%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1% or 0.5% w / w of the pharmaceutical composition.

21. The use according to claim 20, wherein the pharmaceutical composition comprises PS in a concentration less than or equal to 8% w / w of the pharmaceutical composition.

22. The use of claim 21, wherein the pharmaceutical composition comprises PS at a concentration of 5% or 3% w / w of the pharmaceutical composition.

23. The use of claim 20, wherein the pharmaceutical composition comprises PS at a concentration less than or equal to 3% w / w of the pharmaceutical composition.

24. The use of claim 23, wherein the pharmaceutical composition comprises PS at a concentration of 2% or 1% w / w of the pharmaceutical composition.

25. The method of claim 15, wherein the PS is concentrated to 0.005 g / 10 cm 2 Up to 0.25g / 10cm 2 Apply to the affected area.

26. The method of claim 25, wherein the PS is administered at a dose of: 1) 0.005 g / 10 cm 2 affected areas; II) 0.01g / 10cm 2 affected areas; III) 0.05g / 10cm 2 affected areas; IV) 0.1g / 10cm 2 affected areas; V)0.15g / 10cm 2 affected areas; VI) 0.2g / 10cm 2 affected areas; or VII) 0.25g / 10cm 2 affected areas.

27. The use of claim 15, wherein the PS is applied to the affected area and left on the affected area for between 1 hour and 5 hours.

28. The method of claim 27, wherein: (a) applying the PS to the affected area and leaving it on the affected area for 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours or 5 hours; and / or (b) removing the PS from the affected area after the administration period; or applying a second or further application of PS to the affected area after the administration period.

29. The method of claim 15, wherein: a) the PS is applied once a day; b) the PS is applied twice daily; c) the PS is applied three times daily; or d) The PS was applied four times daily.

30. The method of claim 1, wherein: a) treating the neuropathic pain including alleviating or eliminating the neuropathic pain; and / or b) preventing the neuropathic pain includes reducing the incidence of the neuropathic pain.

31. The method of claim 16, wherein: a) the pharmaceutical composition comprising PS is a cream; b) the pharmaceutical composition comprising PS is a gel; c) the pharmaceutical composition comprising PS is an ointment; d) the pharmaceutical composition containing PS is a spray; or e) The pharmaceutical composition comprising PS is formulated as a patch.

32. The use of claim 31 , wherein the gel is a hydrogel.

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