Treating pain associated with diabetic peripheral neuropathy

Abstract

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

Description

[Technical field]

[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.

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

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

[0004] Neuropathy is related to the development of neuropathic pain. Neuropathic pain can occur as a result of 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. Such nerve structures become highly sensitive to stimuli and can generate pulses even in the absence of stimuli. Damage can occur for many reasons, such as diseases such as diabetes (i.e., DPN), chemotherapy treatments, and advanced cancer, viruses (e.g., shingles or HIV), and physical injuries (e.g., accidents or surgery).

[0005] Peripheral nerve lesions can result in pathological conditions characterized by the presence of persistent spontaneous pain, which is often associated with hyperalgesia (increased response to noxious stimuli) and allodynia (pain induced by non-painful stimuli). Hyperalgesia and allodynia are associated with central sensitization, in which CNS nociceptive neurons show increased excitability due to persistent input or a decrease in stimulation threshold induced by peripheral injury. Central sensitization is involved in the development and maintenance of neuropathic pain associated with peripheral neuropathy.

[0006] In terms of symptoms, peripheral neuropathy can cause sharp pain, dull ache, painful burning or cold sensations, abnormal sensations, loss of proprioception, numbness, or even loss of pain sensation.

[0007] There is currently a global need for improved pain therapies, as neuropathic pain has become a major health problem across a wide range of populations.

[0008] Neuropathic pain is often attempted to be treated with so-called non-conventional analgesics, for example antidepressants such as duloxetine and amitriptyline, or anticonvulsants such as gabapentin or pregabalin. In addition, local anesthetics (including lidocaine) are used to treat and manage neuropathic pain. Despite evidence to the contrary, nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to manage neuropathic pain. However, a review of recent clinical trials has not shown any significant pain relief with NSAIDs in patients with neuropathic pain (Moore et al. Cochrane Database of Systematic Reviews (2015); 10: 1-25), and no clinical outcomes showed 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 a peripheral neuropathy caused by diabetes and represents one of the most serious complications of diabetes. Approximately half of 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. These nerves protect the body by sending signals to the brain about pain and changes in temperature, detect touch, pressure, and help maintain balance. Clinical guidelines recommend pain relief in painful diabetic neuropathy through the use of antidepressants (e.g., duloxetine) and / or antiepileptic drugs (e.g., gabapentin and pregabalin), as well as topical agents such as opioids and capsaicin. Current treatments for pain associated with DPN have limited effectiveness and can cause significant side effects.

[0010] Therefore, there is a great need for compounds that treat and / or prevent pain associated with peripheral neuropathy, particularly DPN. Summary of the Invention

[0011] Surprisingly, the present inventors have found that phosphosulindac (PS) is effective in treating and preventing pain associated with DPN.

[0012] PS is a nonsteroidal compound with anti-inflammatory activity. However, PS is not a typical NSAID because it does not inhibit the expression of COX-1 and COX-2, unlike its parent NSAID sulindac. PS has previously been shown to have anti-cancer and anti-inflammatory properties through inhibition of NF-κB activation and alterations in the MAPK signaling branch, and activity in treating rheumatoid arthritis through suppression of key pro-inflammatory signaling pathways in inflammatory mouse models (Mackenzie et al. (2010) Gastroenterology 139(4):1320-32 and Mattheolabakis et al. (2013) Pharm Res 30(6):1471-82). WO2019 / 067919 suggests anti-inflammatory activity of PS in an acute model of dry eye disease (DED). Furthermore, in this model, PS was found to restore ocular sensitivity suppressed in DED, suggesting a role for PS in increasing, rather than decreasing, nociception. Although PS is not a typical NSAID as mentioned above, it showed similar activity to NSAIDs when administered to normal eyes in the DED model. However, these observations cannot suggest a role for PS in the treatment of neuropathic pain associated with DPN. Furthermore, clinical guidance in the field recommends avoiding the use of NSAIDs in the treatment of all types of neuropathic pain, and anti-inflammatory activity alone is considered therapeutically insufficient.

[0013] Nevertheless, the inventors have investigated the activity of PS in specific animal models of neuropathic pain and demonstrated a surprising therapeutic efficacy comparable to that of direct-acting neuroleptic anesthetics (e.g., lidocaine and pregabalin). The specific animal model is important when developing a therapy for neuropathic pain. Indeed, given the pathology of pain associated with peripheral neuropathy, the observed efficacy of a particular compound in an alternative pain model cannot indicate the usefulness of that compound in treating neuropathic pain. In line with this, it is not possible to extrapolate the use of effective drugs from other forms of neuropathic pain to a particular form of neuropathic pain, even if the clinical symptoms are similar. For example, gabapentin shows different efficacy in treating different forms of neuropathic pain. Therefore, the animal model used in early testing before further clinical development is crucial. Based on a specific animal model of DPN neuropathic pain, the observations herein demonstrate the unprecedented efficacy of PS in treating and / or preventing neuropathic pain associated with DPN.

[0014] Thus, in a first aspect, the present invention provides a method for treating and / or 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 treated and / or prevented.

[0015] In some embodiments, PS is the sulfoxide form of PS. Thus, PS can have formula I (PS-I). [ka]

[0016] In other embodiments, the PS is the sulfide form of PS, so that the PS can have the formula II (PS-II). [ka]

[0017] As used herein, the term "phosphosulindac" 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 incorporated herein by reference in its entirety.

[0018] As mentioned above, nerve damage associated with DPN may result in overactivation of pain signaling pathways leading to sensitization of peripheral and / or central neurons, which may exhibit reduced stimulation thresholds. Thus, subjects with DPN may experience pain as a result of this sensitization, for example, pain induced by non-painful stimuli (allodynia) or pain enhanced in response to noxious stimuli (hyperalgesia). Based on the observations herein, PS may have a direct analgesic effect, for example, by reducing neuronal signaling involved in pain sensation. Furthermore, PS may reduce pain that occurs via peripheral sensitization or central sensitization. Thus, PS may reduce or prevent centrally generated pain signaling. PS may reduce or prevent sciatic nerve generated pain signaling. PS may reduce or prevent dorsal root ganglion generated pain signaling. Given that PS has been shown to ascend peripheral neurons toward the spinal cord, PS may reduce or prevent spinal cord generated pain signaling. In some embodiments, the neuropathic pain is allodynia. Allodynia can occur in response to mechanical and / or thermal stimuli. Additionally, in some embodiments, the neuropathic pain is hyperalgesia.

[0019] PS can be formulated into pharmaceutical compositions for use in the present invention.In some embodiments, the pharmaceutical compositions comprise PS and one or more pharma-ceutically acceptable excipients.PS can be formulated for local administration, particularly for local administration to the upper and lower extremities of a subject (i.e., to cover a stocking-glove distribution). [Brief description of the drawings]

[0020] [Figure 1] Schematic diagram of therapeutic trials for DPN-related neuropathic pain. STZ is streptozotocin. PWT is paw withdrawal threshold test. [Diagram 2] Effect of PS on neuropathic pain associated with STZ-induced DPN (compared to vehicle). [Diagram 3] Effects of sulindac, lidocaine, and pregabalin on neuropathic pain associated with DPN. [Figure 4] Schematic diagram of the prevention test for DPN-related neuropathic pain. STZ is streptozotocin. PWT is paw withdrawal threshold test. [Diagram 5] Effect of PS on preventing neuropathic pain associated with DPN. *p<0.0001 (STZ vs. naive); **p<0.004 (PS vs. vehicle); ***p<0.001 (lidocaine vs. vehicle). [Figure 6] Schematic diagram of PS metabolism. [Figure 7] Biodistribution of PS in various tissues after local administration. SN=sciatic nerve. DRG=dorsal root ganglion. [Figure 8-1] Distribution of PS metabolites in various tissues after local administration of PS. SN=sciatic nerve. DRG=dorsal root ganglion. [Figure 8-2] Distribution of PS metabolites in various tissues after local administration of PS. SN=sciatic nerve. DRG=dorsal root ganglion. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] definition The following definitions of pain types are in accordance with the International Association for the Study of Pain (IASP). "Pain" is an unpleasant sensory and emotional experience associated with or resembling 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 (not a diagnosis) and requires a demonstrable lesion or disease that meets established neurological diagnostic criteria. Patients with neuropathic pain may experience one or more sensations described as heating, burning, throbbing, electric shocks, stabbing, sharp pain, cramping, aching, tingling, numbness, or prickling. The term "lesion of the somatosensory nervous system" is generally used when diagnostic testing (e.g., imaging, neurophysiological testing, biopsy, laboratory tests) reveals an abnormality or when obvious trauma has been noted. The term "disease of the somatosensory nervous system" is generally used when the underlying cause of the lesion (e.g., stroke, vasculitis, diabetes, genetic abnormality) is known. "Peripheral neuropathic pain" is pain caused by lesions or disease of the peripheral somatosensory nervous system. "Central neuropathic pain" is pain caused by lesions or disease of the central somatosensory nervous system. "Central sensitization" refers to increased responsiveness of nociceptive neurons in the central nervous system to normal or subthreshold afferent input. "Peripheral sensitization" refers to increased responsiveness and lowered threshold of nociceptive neurons in the periphery to stimulation of receptive fields. "Allodynia" is pain due to stimuli that do not normally induce pain. "Hyperalgesia" is increased pain due to stimuli that normally induce pain.

[0022] Generally, the term "disease" refers to an existing condition or state of a patient or subject that can be treated using the methods provided herein.

[0023] The term "therapeutically effective amount" refers to an amount of a compound or combination of compounds described herein sufficient to exert an effect of the intended application, including but not limited to, treatment and / or prevention of a disease.

[0024] "Pharmaceutically acceptable excipient" is intended to include any solvent, dispersion medium, coating agent, antibacterial and antifungal agent, isotonic and absorption retardant, and inactive ingredients contained in a pharmaceutical composition. The use of such pharmaceutically acceptable excipients for the formulation of active pharmaceutical ingredients is well known in the art. Any conventional pharmaceutically acceptable excipient is intended to be used in the therapeutic composition of the present invention, except in the case where it is incompatible with PS.

[0025] Use of the term "about" when referring to a numerical value is optional and means that the number referred to is an approximation within typical experimental variation (or within statistical experimental error), and therefore the number may vary accordingly.

[0026] The term "comprising" encompasses "including" and "consisting", e.g., a composition "comprising" X may consist of only X or may include something additional (e.g., X+Y).

[0027] Pain Associated with Diabetic Peripheral Neuropathy Pathologies occurring in diabetic patients, particularly hyperglycemia, can cause damage to neurons, resulting in peripheral neuropathy and associated neuropathic pain. Neuropathic pain in these patients develops over time, is often worse in patients with long-standing disease, and can include stabbing, 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. Because DPN develops over time in diabetic patients, subjects may experience worsening neuropathic pain over time, and therefore subjects would benefit from an analgesic that can treat ongoing neuropathic pain as well as prevent further neuropathic pain from developing. Thus, in some embodiments, PS can be used to treat and prevent neuropathic pain associated with DPN. In line with the above, the present invention provides PS for use in the treatment and / or prevention of neuropathic pain associated with DPN. Further, the present invention also provides the use of PS for the manufacture of a medicament for the treatment and / or prevention of neuropathic pain associated with DPN.

[0028] Based on the observations herein, PS has a direct analgesic effect on DPN-associated neuropathic pain. DPN-associated neuropathic pain can be stabbing, burning, and / or piercing pain. DPN patients can experience constant symmetric neuropathic pain in the lower and upper limbs. In treating DPN-associated neuropathic pain, PS can reduce or eliminate neuropathic pain. In treating DPN-associated neuropathic pain, PS can also reduce or eliminate one or more of the sensory symptoms associated with DPN. In preventing DPN-associated neuropathic pain, PS can reduce the occurrence of neuropathic pain. In preventing DPN-associated neuropathic pain, PS can also reduce the occurrence of one or more of the sensory symptoms associated with DPN.

[0029] Sensory symptoms of DPN include numbness (e.g., numbness, tingling, prickling, or formication), burning, or electric shock (i.e., electric shock-like) sensations. DPN usually affects the extremities, such as the feet, hands, legs, and arms, where nerve fibers are the longest and most numerous, and patients often have a "stocking-and-glove" distribution. Even if the sensory symptoms experienced by subjects with DPN are not painful (or do not reach the threshold required to be considered as pain per se), PS can be used to reduce, eliminate, or reduce the occurrence of any one or more of the sensory symptoms experienced by subjects with DPN, including those listed above. PS can be used to reduce, eliminate, or reduce the occurrence of stocking-and-glove distribution in DPN patients.

[0030] As mentioned above, neuropathic pain associated with DPN may be the result of central sensitization, which results in allodynia and / or hyperalgesia. PS can reduce, eliminate or reduce the occurrence of neuronal signaling involved in pain sensation in DPN patients. PS can reduce, eliminate or reduce pain that occurs through peripheral sensitization or through central sensitization. Thus, PS can reduce, eliminate or reduce the occurrence of centrally generated pain signaling. PS can reduce, eliminate or reduce pain signaling that occurs in the sciatic nerve. PS can reduce, eliminate or reduce pain signaling that occurs in the dorsal root ganglion. Given that PS has been shown to ascend peripheral neurons toward the spinal cord, PS can reduce, eliminate or reduce the occurrence of pain signaling that occurs in the spinal cord. Neuropathic pain in DPN patients can be allodynia (e.g., mechanical allodynia or thermal allodynia). Additionally or alternatively, neuropathic pain in subjects with DPN can be hyperalgesia.

[0031] Neuropathic pain in DPN patients can be measured by visual analog pain scale or using any other suitable method in the art.

[0032] Pharmaceutical Compositions The PS for use in the methods of the present invention can be formulated into a pharmaceutical composition suitable for administration to a subject with DPN. Typically, the pharmaceutical composition is formulated to provide a therapeutically effective amount of PS and can further include a pharma- ceutical acceptable excipient.

[0033] Neuropathic pain associated with DPN can occur in various parts of the body. However, as outlined above, DPN tends to affect the peripheral nerves of the upper and lower limbs, i.e., the extremities, which explains the "stocking-glove" distribution experienced by these patients. Therefore, a particularly useful pharmaceutical composition comprising PS is a pharmaceutical preparation that can be applied directly to the peripheral site where neuropathic pain is experienced (e.g., the upper and lower limbs of a subject). Furthermore, a pharmaceutical composition comprising PS can be applied to the location where one or more sensory symptoms of DPN are experienced. Thus, a pharmaceutical composition comprising PS can be formulated for topical administration. In particular, a pharmaceutical composition comprising PS can be formulated for transdermal administration, particularly to the skin of the upper and / or lower limbs of a subject.

[0034] In some embodiments, the pharmaceutical composition comprising PS can be formulated as a semi-solid or liquid. Thus, the pharmaceutical composition comprising PS can be formulated as a cream, gel (e.g., hydrogel), lotion, ointment, foam, and / or spray. These compositions have different relative concentrations of oil and water, which results in the compositions having different densities. Altering the density of the formulation is a means by which the exposure of the affected area to the pharmaceutical composition can be controlled. For example, a formulation with a relatively low density may require rubbing until absorbed, resulting in a short exposure time. Alternatively, a formulation with a relatively high density may not be absorbed as easily, thereby allowing a longer exposure of the affected area to the pharmaceutical crude. Those skilled in the art will recognize that topical pharmaceutical compositions can be formulated to alter the relative exposure of the affected area to the active pharmaceutical ingredient.

[0035] In another embodiment, the pharmaceutical composition comprising PS can be formulated as a patch that can be applied to the skin. The patch can be manufactured in a manner that ensures a controlled release of PS to the affected area.

[0036] Formulations suitable for topical administration and suitable pharma- ceutically acceptable excipients are well known in the art. Exemplary formulations for topical administration are set forth in WO2019 / 067919, which is incorporated herein by reference in its entirety.

[0037] In some embodiments, a formulation of PS suitable for topical administration may include PS at a concentration of about 0.5% w / w to about 15% w / w of the pharmaceutical composition. Thus, PS may be present 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. As an illustrative example, PS may be present at a concentration of 8% w / w or less of the pharmaceutical composition, for example, about 5% w / w of the pharmaceutical composition, particularly about 3% w / w of the pharmaceutical composition, when formulated as a topical cream. By way of further illustration, when formulated as a gel, the PS may be present at a concentration of 8% w / w or less of the pharmaceutical composition, for example, 5% w / w or less of the pharmaceutical composition, particularly 3% w / w or less of the pharmaceutical composition, for example, about 2% or about 1% w / w of the pharmaceutical composition. In certain formulations, the PS may be present at a concentration of 5% w / w of the pharmaceutical composition, for example, when formulated as a hydrogel or ointment.

[0038] A single application to both hands (i.e., gloves) may require less than about 5 ml of the pharmaceutical composition, e.g., 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., socks) may require less than about 6 ml of the pharmaceutical composition, e.g., about 4 ml of the pharmaceutical composition (i.e., about 2 ml of the pharmaceutical composition per foot).

[0039] Alternatively, the pharmaceutical composition comprising PS may be formulated for any other administration form 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.

[0040] Dosing regimen The appropriate dosing regimen of PS for the treatment and / or prevention of DPN will depend on variables such as the type and progression of pain (e.g., as defined by 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 excipient formulation, the route of administration, and the judgment of the attending physician.

[0041] For local administration, PS can be administered to cover one or more affected areas, for example, the upper and lower extremities of a subject. In some embodiments, about 0.01 to about 5 g of PS can be administered to the affected area. In terms of the size of the affected area, PS can be administered in an amount of about 0.005 to 0.25 g / 10 cm. 2 Therefore, PS can be administered at the affected area at a dose of approximately 0.005 g / 10 cm 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 It can be administered at the affected site.

[0042] In some cases, PS for use in topical administration can be applied and then removed (e.g., by washing off) from the affected area and then reapplied. In some cases, the PS is washed off after a period of time. Alternatively, since the analgesic effect may decrease over time and require readministration, in some cases, rather than washing off the PS, the PS is reapplied to the affected area after an appropriate administration period has elapsed. For example, the PS can be applied to the affected area and left on the affected area for about 0.5 hours to about 5 hours (before removal or reapplication). Thus, the PS can be applied topically and left on the affected area for about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours (before removal or reapplication).

[0043] Because the neuropathic pain associated with DPN is chronic, repeated local administration of PS is necessary. Thus, PS can be applied topically one to four times per day. Thus, PS can be applied once per day, twice per day, three times per day, or four times per day. For certain formulations of PS, e.g., hydrogels or ointments with a PS concentration of about 5% w / w of the pharmaceutical composition, the formulation can be applied topically three times per day. In more severe cases, PS can be further applied about 0.5 hours after each application.

[0044] Since PS can have a long-lasting analgesic effect, it can be administered less frequently.For example, PS can be administered locally less than once a day, for example, once every two days.In fact, for patients who experience long-term analgesic effect from a single administration, PS can be administered locally less than once a week, for example, once every two weeks.

[0045] For topical administration of some pharmaceutical compositions, it is useful to cover the affected area with, for example, a bandage (e.g., plastic wrap or film) after applying the pharmaceutical composition, for example, to ensure that an appropriate amount of the composition is applied for an appropriate period of time. Therefore, after topical application of PS, a bandage may be applied to the affected area.

[0046] In some embodiments, the PS can be administered topically in the form of a patch (e.g., a medicated salve). The use of a patch can reduce the administration interval and / or frequency, for example, because the patch ensures a 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.

[0047] Administration of PS can be continued as long as necessary. For example, PS can be administered for more than 1 day, more than 2 days, more than 3 days, more than 4 days, more than 5 days, more than 6 days, more than 7 days, more than 14 days, more than 28 days, more than 56 days, or more than 84 days. As mentioned above, PS can be administered chronically for the treatment of chronic effects, for example, for at least 3 months. Thus, in some cases, continuous administration is achieved and maintained as long as necessary. PS can be administered intermittently depending on the recurrence of neuropathic pain and / or associated sensory symptoms.

[0048] The PS can be used to treat and / or prevent DPN in a mammal. For example, the subject can be a human.

[0049] As described above, PS can be formulated into a pharmaceutical composition suitable for administration to DPN patients. Thus, PS can be administered in a suitable pharmaceutical composition according to the above-mentioned administration regimen.

[0050] Those skilled in the art will understand that in certain embodiments, the dosage of such compounds may be adjusted according to the mammalian subject of treatment. For example, the treatment of rats is described herein, but such dosage may or may not be modified when PS is administered to humans. However, those skilled in the art can convert the dosages shown herein as necessary, as described in Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, USDepartment 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 from the animal dose and can be obtained in mg / kg by multiplying the animal dose by the following conversion factors: 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, micropig=0.73, and minipig=0.95.

[0051] Pharmaceutically acceptable forms of PS A pharmaceutical composition comprising PS can include a pharma- ceutically acceptable form of PS, which can be a solvate, derivative, and / or prodrug.

[0052] solvate 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. When the solvent is water, the solvate is a hydrate. Pharmaceutically acceptable forms of PS include solvates of PS, such as solvates of PS-I and / or PS-II. In some embodiments, the solvate comprises at least one molecule of solvent. In some embodiments, the solvate comprises less than one molecule of solvent. In some embodiments, the solvate is a hydrate.

[0053] Isotopes Pharmaceutically acceptable forms of PS can include isotopically labeled derivatives of PS-I. Pharmaceutically acceptable forms of PS can include isotopically labeled derivatives of PS-II. An isotopically labeled derivative is a compound identical to PS except that one or more atoms are replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. In some embodiments, an isotopically labeled derivative of PS includes one or more isotopes of hydrogen, carbon, oxygen, phosphorus, and fluorine. In some embodiments, an isotopically labeled derivative of PS includes one or more isotopes of hydrogen, carbon, oxygen, phosphorus, and fluorine, respectively. 2 H, 3 H, 13 C. 14 C. 18 O. 17 O. 31 P, 32 P, 35 S, and 18 In some embodiments, the isotopically labeled derivative of PS comprises one or more isotopes of F. 2 In some embodiments, the isotope-labeled derivative of PS comprises one or more isotopes of H (e.g., deuterium). 3 In some embodiments, the isotope-labeled derivative of PS comprises one or more isotopes of H (e.g., tritium). 14 Contains C isotopes.

[0054] Derivatives and Prodrugs A pharma- ceutically acceptable form of PS can include a derivative of PS-I. A pharma-ceutically acceptable form of PS can include a derivative of PS-II. In some embodiments, a derivative of PS (e.g., PS-I or PS-II) is a metabolite. In other embodiments, a pharma-ceutically acceptable form of PS is a prodrug of PS (e.g., a prodrug of PS-I or a prodrug of PS-II).

[0055] The sulfone group can be structurally represented as RS(=O)2-R'. In some embodiments, the derivative of PS is the sulfone form of PS.

[0056] PS comprises an organophosphate functional group, which can be structurally represented as O=P(OR)3, O=P(OR)2(OR'), or O=P(OR)(OR')(OR''). For example, O=P(OR)2(OR') can correspond to PS where R=CH2CH3 and R'=the remainder of the molecule conforms to PS of Formula I or II (e.g., PS-I, PS-II, or derivatives thereof).

[0057] In some embodiments, the derivative of PS is PS in which one of the ethoxy (e.g., -OCH2CH3) groups is an OH group, or a pharma- ceutically acceptable salt thereof. In some embodiments, the derivative of PS is PS in which both ethoxy (e.g., -OCH2CH3) groups are OH groups, or a pharma- ceutically acceptable salt thereof.

[0058] The activities of PS demonstrated herein are believed to be shared by its pharma- ceutically acceptable forms, and therefore the invention provides pharma- ceutically acceptable forms of PS for use in the methods of the invention.

[0059] While preferred embodiments of the present invention have been 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 can be employed in practicing the invention. EXAMPLES

[0060] The embodiments encompassed herein will now be described with reference to the following examples, which are provided for illustrative purposes only, and the disclosure encompassed herein should not be construed as being limited to these examples in any way, but rather as encompassing any variations that become evident as a result of the teachings provided herein.

[0061] Example 1: Effect of PS in a rat model of DPN DPN was induced in rats by chemically inducing elevated blood glucose with streptozotocin (STZ), a well-established model of DPN (see Morrow, Current Protocols in Neuroscience (2004); 29(1):1-11), in which STZ, an antibiotic extracted from Streptomyces acromogenes, selectively damages pancreatic beta cells. As demonstrated, PS is effective in treating DPN, where treatment is initiated after establishment of neuropathy.

[0062] method Sprague-Dawley rats were fasted for 4-6 hours and then injected intraperitoneally with 45 mg / kg STZ. This was done for all experimental groups except the naïve group. To prevent death from hypoglycemia, rats were given 10% sucrose water as their only source of water for the first 48 hours after injection. Blood glucose levels were measured 72 hours after STZ injection to ensure that only rats considered diabetic (i.e., non-fasting plasma glucose levels >250 mg / dL) were included in the study.

[0063] Four weeks after STZ injection, rats were randomized and assigned to treatment groups as shown in Figure 3. This delay between STZ injection and treatment allows the establishment of chronic pain (allodynia) associated with peripheral and central sensitization. PS (8% hydrogel) or vehicle control was administered topically to both hind paws of rats three times a day for three weeks, starting four weeks after STZ injection. 0.7% sulindac hydrogel was applied three times a day for one week (this is the safest sulindac concentration for these animals). 5% lidocaine cream (positive control) was applied to both hind paws of rats only once, 30 minutes before PWT measurement. Finally, a further positive control, pregabalin (10 mg / kg) or its vehicle, was orally administered only once, 1 hour before PWT measurement.

[0064] The rats were divided into eight experimental groups. The experimental groups (1-4) had an average body weight of approximately 225 g, and the control groups (5-8) had an average body weight of approximately 335 g. The experimental groups were as follows: 1. Group 1: Naive rats (n=5) 2. Group 2: STZ only (n=6) 3. Group 3: STZ + vehicle (n = 6) 4. Group 4: STZ + PS (8% hydrogel) (n = 7) 5. Group 5: STZ + oral vehicle (n=8) 6. Group 6: STZ + 0.7% sulindac hydrogel (n=7) 7. Group 7: STZ + 5% lidocaine cream (n=8) 8. Group 8: STZ + pregabalin (10 mg / kg) (n=7)

[0065] To determine the outcome of the treatment, mechanical allodynia was measured using a well-established method, von Frey filaments. In particular, a simplified up-down method for estimating paw withdrawal threshold (PWT) using von Frey filaments was used (described in Bonin et al., Molecular Pain (2014); 10(26): 1-10). The results of the PWT test are expressed as applied force (gm). PWT tests were performed at weeks 4, 5, and 7 depending on the administration protocol, with the first measurement taken as baseline (i.e., demonstrating the effectiveness of STZ in establishing DPN). Measurements at weeks 5 and 7 were performed 30 minutes after the final treatment with Sulindac or PS, respectively. For completeness, differences in the mean body weights of rats in the experimental and control groups do not affect the ability to compare the results from these groups (i.e., rats are simply obtained from different batches and respond in the same way to the experimental procedures).

[0066] Figure 1 shows an overview of the study.

[0067] result As shown in Figure 2, administration of STZ resulted in a significant decrease in PWT after 4 weeks of treatment (p<0.02 vs. naive rats). Thus, this model established DPN-related pain as expected. Addition of vehicle did not have a significant effect on PWT compared to STZ alone, and the decrease in PWT compared to naive rats was similar to 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). Values ​​corresponding to Figure 2 are shown in Table 1. [Table 1]

[0068] Furthermore, as shown in Figure 3, neither vehicle nor sulindac administration was able to inhibit the PWT reduction caused by STZ (sulindac was not significantly different from vehicle). However, both lidocaine and pregabalin achieved a significant increase in PWN compared to vehicle (p<0.03 and p<0.009, respectively). The values ​​corresponding to Figure 3 are shown in Table 2. [Table 2]

[0069] conclusion Local administration of PS is effective in normalizing diabetes-induced neuropathic pain in the most reliable animal model of diabetes. Indeed, PS significantly increased PWT in rats exhibiting STZ-induced neuropathic pain. Therefore, PS treats neuropathic pain associated with DPN.

[0070] While PS was effective, strikingly, the non-phosphorylated "parent" sulindac (a typical NSAID) failed to achieve rescue of PWT and therefore failed to treat DPN-associated pain in a rat model. This was despite sulindac being administered at the maximal nontoxic 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, significantly reduced DPN-associated pain. Thus, the efficacy observed with locally administered PS is closer to that of the centrally acting positive control than to its closely related parent compound.

[0071] Thus, PS may act mechanistically differently from its parent NSAIDs and more like a centrally acting agent. These observations serve to demonstrate the potential of PS in established neuropathic pain associated with DPN.

[0072] Example 2: Preventive effect of PS on neuropathic pain in a rat model of DPN DPN was induced in rats by chemically inducing elevated blood glucose with streptozotocin (STZ). To establish a preventive model, treatment with PS (sulindac or vehicle) was started on day -2, followed by STZ (day 0). PS, unlike sulindac, has been demonstrated to be effective in preventing neuropathic pain associated with DPN.

[0073] method The animal model corresponded to that used in Example 1, but was performed using a prophylactic protocol. As in Example 1, the outcome measure to determine the efficacy of treatment in preventing mechanical allodynia was the PWT test with von Frey filaments. Measurements were performed on day -3, before treatment or induction of DPN-related neuropathic pain, and again at the end of the study period (day 28).

[0074] Rats were randomly assigned to treatment groups as follows, all with an average body weight of approximately 225 g: 1. Group 1: Naive rats (n=6) 2. Group 2: STZ only (n=8) 3. Group 3: STZ + vehicle (n = 8) 4. Group 4: STZ+PS 8% (n=8) 5. Group 5: STZ + sulindac 0.7% (n=8) 6. Group 6: STZ + lidocaine cream 5% (n=8)

[0075] To determine the baseline of mechanical allodynia, each treatment group was subjected to PWT assessment on day -3. Then, depending on the treatment group, rats were started on a treatment regimen of PS (8% hydrogel), Sulindac (0.7% hydrogel), or vehicle, which was applied topically to both hind paws of the rats three times a day starting on day -2 and continued until day 28. Rats in the lidocaine treatment group received a single application of lidocaine cream to both hind paws 30 min before the final PWT measurement on day 28. On day 0, DPN-related neuropathic pain was induced by administration of STZ, and blood glucose was checked on day 3. Four weeks after administration of STZ, rats were subjected to paw withdrawal threshold testing to provide sufficient time for the development of DPN-related neuropathic pain (manifested as mechanical allodynia) (see STZ-only group in Figure 5).

[0076] Figure 4 shows an overview of the study.

[0077] result As shown in FIG. 5, administration of STZ resulted in a significant decrease in PWT after 4 weeks of administration (p<0.0001 vs. naive rats). Thus, in this model, neuropathic pain associated with DPN was established as achieved in Example 1. Additional administration of vehicle had no significant effect on PWT compared to STZ alone. However, administration of PS achieved a significant increase in PWT compared to vehicle (p<0.004), returning PWT to the threshold observed in naive rats. The effect of PS on PWT was comparable to that achieved with lidocaine, significantly increasing PWT compared to vehicle (p<0.001). However, administration of sulindac did not show a significant effect on PWT compared to vehicle. In fact, PS showed a significant effect on PWT compared to that achieved by sulindac.

[0078] The values ​​corresponding to FIG. 5 are shown in Table 3. [Table 3]

[0079] conclusion Similar to the observations regarding the treatment experiments in Example 1, local administration of PS is effective in preventing neuropathic pain associated with DPN, as demonstrated by a significant increase in PWT in rats treated with prophylactic PS.

[0080] In contrast to PS, sulindac (again, at the maximal nontoxic dose, administered in a regimen and frequency corresponding to that used for PS) failed to prevent DPN-associated neuropathic pain. The positive control lidocaine, known to have a central site of action for analgesia, effectively prevented DPN-associated neuropathic pain and achieved a normalization of PWT similar to that achieved by PS. Thus, the preventive efficacy observed with locally administered PS is closer to that of a centrally acting positive control than to its closely related parent compound, sulindac.

[0081] Thus, supporting the observations in Example 1, this study confirms that PS is mechanistically distinct from its parent NSAIDs in a prophylactic setting and demonstrates similar therapeutic efficacy to centrally acting lidocaine. These observations serve to support the potential of PS in preventing neuropathic pain associated with DPN.

[0082] Example 3: Pharmacokinetics and biodistribution of PS Given the ability of PS to treat and prevent neuropathic pain associated with DPN, especially with efficacy comparable to centrally acting drugs (e.g., pregabalin and lidocaine), we investigated the site of action of PS. We found that PS traverses intraneurons from the periphery to the spinal cord, despite being administered locally.

[0083] method PS 8% ointment was applied topically to the hind paws (50 μl per paw) and gently rubbed in. At 0.5, 1, 3, 5, 12, 18, and 24 hours, mice (n=4-5 / time point) were euthanized by CO2 inhalation. Blood was collected immediately after death. Tissues including paw skin, foot muscle, leg muscle, sciatic nerve, and lumbar DRG were quickly dissected bilaterally, immediately frozen in liquid nitrogen, and stored at -80°C until analysis.

[0084] As previously described (Wen et al., Int J Pharm (2019); 557: 273-279), each plasma sample was mixed with 2 volumes of acetonitrile and centrifuged at 13,200 rpm for 15 min. Tissue samples were weighed, ddH2O (100–300 μL, depending on tissue weight) was added, and these were homogenized. After adding acetonitrile (2x the volume of the homogenate), the mixtures were sonicated for 10 min, centrifuged at 13,200 rpm for 15 min, and analyzed by HPLC as reported (Wen et al., 2019). The limits of quantification were 0.1 μM for PS and 0.05 μM for sulindac, sulindac sulfone, sulindac sulfide, and their glucuronic acid derivatives.

[0085] result PS can be rapidly metabolized in vitro and in vivo to several metabolites, including PS sulfide, PS sulfone, sulindac, sulindac sulfide, and sulindac sulfone (Figure 6). The glucuronide of sulindac and its metabolites (formed primarily in the liver) have also been identified. Because the metabolism and PK / biodistribution of PS differ depending on its route of administration, we investigated both in normal mice administered PS locally to the hind paw, with particular focus on the sciatic nerve and dorsal root ganglion (DRG), which are affected in DPN.

[0086] As shown in Figure 7 and Table 4, PS was detected in the foot skin, application site, muscle under the skin, leg muscle, sciatic nerve, and DRG. As expected (Xie et al. Br J Pharmacol (2012a); 165: 2152-2166), PS was not detected in the systemic circulation.

[0087] The concentration of PS is C max (194.7±5.3μM~0.3±0.1μM) and AUC 0-24h The T of PS gradually decreased from the skin to the DRG, which is the furthest from the skin, as evident from the respective values ​​of both (1,609.8 μM h−1 and 4.5 μM h−1). max was the same for all tissues (0.5 hours), except for the DRG, which had a long T max The results showed that the PS was activated in the skin and muscle at 18 h after stimulation with β-glucose (β-glucose) and β-glucose (β-glucose) ... 1 / 2 , within a relatively narrow range (11.4–20.6 h), in contrast to the much longer value of 57.4 h in the sciatic nerve and possibly even longer in the DRG (which could not be quantified with reasonable precision).

[0088] These differences indicate that there is a difference in metabolic capacity for PS between nerves and skin and muscle. [Table 4]

[0089] Only three metabolites of PS were detected: sulindac, sulindac sulfone, and sulindac sulfide (Figure 8 and Table 5). No glucuronic acid products were detected. Sulindac was the quantitatively predominant metabolite, with sulindac sulfide and sulindac sulfone levels less than 20% of the sulindac level. Sulindac levels were around 25% of PS in all tissues except sciatic nerve (higher) and DRG (equal). [Table 5]

[0090] Sciatic nerve (C max = 0.9 ± 0.1 μM; AUC 0-24h = 12.0 μM h) and DRG (C max= 0.3 ± 0.1 μM; AUC 0-24 The presence of small amounts of PS at 1000–1500 nm (h = 4.5 μM h) is of particular interest as both are targets of neuropathic pain associated with DPN. max The significantly higher PS concentration in the DRG compared to all other sites and the lower PS levels in the DRG compared to the sciatic nerve suggest that PS reached the DRG by traversing from the skin to the sciatic nerve.

[0091] conclusion These experiments demonstrate that locally administered PS can reach the major sites of action (i.e., the sciatic nerve and dorsal root ganglion) known to be involved in the generation of neuropathic pain associated with DPN. Furthermore, given its rapid metabolism in the bloodstream, these results demonstrate that PS traverses along peripheral neurons (e.g., the sciatic nerve) toward the central nervous system and is found in meaningful concentrations in the DRG. Thus, without wishing to be bound by theory, these observations support that PS exerts its analgesic activity directly on neurons and possibly also within a central site of action, similar to the activity of centrally acting analgesics such as lidocaine and pregabalin. This site of action reflects the comparable efficacy of PS to pregabalin and lidocaine in treating and preventing neuropathic pain associated with DPN observed above.

[0092] Example 4: Summary of Observations The observations herein demonstrate unprecedented analgesic activity of PS in the prevention and treatment of neuropathic pain associated with DPN using a well-established animal model. Thus, the above experiments demonstrate that PS can suppress the signal transduction of neuropathic pain caused by DPN. When administered locally, PS has been shown to track upward along peripheral neurons (e.g., sciatic nerve) toward the spinal cord, and can achieve significant analgesic effects on neuropathic pain associated with DPN. Local administration results in low systemic clearance, reduced drug interactions, increased patient tolerability, and easy combination with oral medications.

[0093] These observations demonstrate previously unrecognized activity and therapeutic utility of PS. Although PS is a compound within the broader NSAID classification, it does not share all the properties of this compound family. Indeed, the data herein demonstrate that, in contrast to the observations for the NSAID sulindac, the activity of PS is more similar to analgesics that directly target neuronal activity, with the potential to act at both peripheral and central sites. Indeed, the above results support that PS can reduce pain resulting from allodynia. Allodynia is known to include pain that arises through peripheral and central sensitization. This model was established 4 weeks prior to treatment randomization, thus clearly establishing the central sensitization demonstrated by allodynia. Thus, without wishing to be bound by theory, PS exerts a direct effect on neuronal pain signaling, which is similar to the established mechanism of action of anesthetic drugs. Indeed, the results demonstrate the ability of PS to reduce pain signaling from peripheral and central sensitization, linking both peripheral and central sites of action to the analgesic activity of this compound, which, of course, is distinct from the established role of PS and typical NSAIDs as anti-inflammatory agents.

[0094] Previous observations on the activity of PS are limited to anti-inflammatory activity. For example, WO2019 / 067919 suggests a role for PS in the treatment of DED using an acute DED model in which concanavalin A (ConA) is administered simultaneously with PS to the lacrimal glands of rabbits. In this context, the anti-inflammatory activity of PS results in a limited inflammatory response to ConA, thus preventing the establishment of DED. These observations support the anti-inflammatory activity of PS and suggest its usefulness in preventing the establishment and maintenance of the inflammatory component of DED. The observations in this acute DED model do not provide any evidence of the ability of PS to act directly on nerves to reduce neuronal signaling caused by neuropathic pain. Any reduction in pain in this acute DED model can only be attributed to PS inhibiting the inflammatory response (i.e., the pathology responsible for inducing the activation of pain sensors). Indeed, the results of the DED model suggest that PS improves corneal sensitivity. This represents an increase in nociception, the opposite effect to that desired for analgesics. Of course, regardless of any indications of analgesic activity of PS, such activity observed in acute DED models does not indicate a corresponding activity in neuropathic pain, and certainly not in the neuropathic pain associated with DPN.

[0095] The experiments herein were carried out using a specific animal model for neuropathic pain associated with DPN. As outlined above, the use of an appropriate animal model is crucial to demonstrate the potential efficacy of a compound in a particular type of neuropathic pain. The efficacy of a drug on pain caused by peripheral neuropathy cannot be extrapolated from its efficacy on other forms of pain, or even other forms of neuropathic pain. Indeed, certain forms of neuropathic pain have different pathologies, and therefore require therapeutic agents with different activities for their treatment and / or prevention. Therapies need to be designed according to the pathophysiology of neuropathic pain and tested in appropriate models. For example, DPN causes extensive nerve damage due to metabolic abnormalities of diabetes (including microvascular ischemia, increased activity in the polyol pathway of glucose metabolism, activation of protein kinase C, lack of insulin-mediated neurotrophic effects, and alterations in the fatty acid pathway), while other neuropathies may result from demyelination (e.g., due to administration of toxic chemotherapeutic agents) or defects in calcium metabolism. Therefore, the effect on both large and small fibers is different between DPN and other forms of neuropathy based on their pathophysiology.The only reliable determination of the effectiveness of a compound in treating the neuropathic pain caused by such pathophysiology is to test the compound in the appropriate neuropathic pain model of DPN, as shown above.Without these observations, there is no indication of any pain-relieving activity of PS in the neuropathic pain associated with DPN.

[0096] The observations herein demonstrate that PS has therapeutic utility beyond that suggested for typical NSAIDs. Indeed, Moore et al. (Cochrane Database of Systematic Reviews (2015); 10: 1-25) have reviewed that NSAIDs have no therapeutic efficacy in peripheral neuropathic pain. The differential activity of PS compared to typical NSAIDs is confirmed by comparison with the parent compound sulindac in the above experiments. Sulindac was unable to reduce established allodynia (i.e., caused by sensitization of peripheral and central neurons). This indicates that sulindac, unlike PS, does not exert a direct analgesic effect on damaged neurons in neuropathic pain caused by DPN. The reason why no response was observed to sulindac in this model is probably because the pain is caused by neuropathic nerve damage after allodynic pain is established, rather than 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 is not shared with closely related NSAIDs. Based on the observations herein about sulindac, any of the alleged analgesic activities of NSAIDs observed in the prior art reflects anti-inflammatory activity (i.e., blocking the initial trigger that causes pain) rather than actual analgesic activity on nerve signaling (i.e., resulting in a reduction in pain caused by nerve damage and sensitization). Indeed, if typical NSAIDs (e.g., sulindac) could directly act on neurons that have analgesic activity, it would be expected that sulindac would reduce allodynia as observed in the above model.

[0097] Thus, the inventors have demonstrated a novel and surprising activity of PS in the treatment and / or prevention of neuropathic pain associated with DPN. As outlined above, this activity exceeds the anti-inflammatory activity previously observed for PS and related NSAIDs. Indeed, the observations herein demonstrate that, unlike typical NSAIDs, PS has direct activity on the peripheral and central nervous system, similar to the site and mechanism of action of analgesics such as lidocaine and pregabalin. Furthermore, PS represents an improved treatment for neuropathic pain associated with DPN, even compared to these centrally acting analgesics, due to its ease of administration (e.g., locally) and limited adverse effects (Mackenzie et al. (2010) Gastroenterology 139(4):1320-32).

[0098] It will be understood that the inventors' approach has been described above by way of example only and that modifications can be made whilst remaining within the scope and spirit of the invention.

Claims

1. A pharmaceutical composition comprising a therapeutically effective amount of phosphoserine (PS) for treating and / or preventing neuropathic pain associated with diabetic peripheral neuropathy (DPN).

2. a) Treating the neuropathic pain comprises reducing or eliminating the neuropathic pain, b) Preventing the neuropathic pain comprises reducing the occurrence of the neuropathic pain, c) Treating the neuropathic pain comprises reducing or eliminating one or more of the sensory symptoms associated with DPN, d) Preventing the neuropathic pain comprises reducing the occurrence of one or more of the sensory symptoms associated with DPN, optionally, the one or more sensory symptoms are selected from allodynia, burning sensation, and shock-like sensation, and the allodynia includes one or more of, for example, numbness, tingling, prickling, or crawling sensation, The pharmaceutical composition according to claim 1.

3. a) PS reduces, eliminates, or decreases the occurrence of neuronal signal transduction involved in the sensation of pain, b) PS reduces, eliminates, or decreases the occurrence of pain caused through peripheral sensitization, c) PS reduces, eliminates, or decreases the occurrence of pain caused through central sensitization, and / or d) PS reduces, eliminates, or decreases the occurrence of centrally generated pain signal transduction, The pharmaceutical composition according to claim 1.

4. a) The PS reduces, eliminates, or decreases the occurrence of pain signal transduction occurring in the sciatic nerve, and / or b) PS reduces, eliminates, or decreases the occurrence of pain signal transduction occurring in the dorsal root ganglion, The pharmaceutical composition according to claim 1.

5. a) The neuropathic pain is allodynia, optionally, the allodynia is mechanical allodynia and / or thermal allodynia, and / or b) The neuropathic pain is hyperalgesia, The pharmaceutical composition according to claim 1.

6. The pharmaceutical composition according to claim 1, wherein the subject is a human.

7. PS has the formula I (PS-I): 【Chemical Formula 1】 The pharmaceutical composition according to any one of claims 1 to 6.

8. PS has the formula II (PS-II): 【Chemical 2】 The pharmaceutical composition according to any one of claims 1 to 6.

9. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition containing PS further comprises a pharmaceutically acceptable excipient.

10. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition containing PS is formulated for topical administration.

11. a) The pharmaceutical composition containing PS is formulated as a semi-solid, b) The pharmaceutical composition containing PS is formulated as a liquid, c) The pharmaceutical composition containing PS is a cream, d) The pharmaceutical composition containing PS is a gel, for example, the gel is a hydrogel, e) The pharmaceutical composition containing PS is a lotion, f) The pharmaceutical composition containing PS is an ointment, g) The pharmaceutical composition containing PS is a spray, or h) The pharmaceutical composition containing PS is formulated as a patch, The pharmaceutical composition according to claim 10.

12. The pharmaceutical composition contains PS at a concentration of about 0.5% to about 15% w / w of the pharmaceutical composition, Optionally, the pharmaceutical composition contains PS at a concentration of about 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, For example, a) The pharmaceutical composition contains PS at a concentration of 8% w / w or less of the pharmaceutical composition, for example, at a concentration of about 5% or about 3% w / w of the pharmaceutical composition, or b) The pharmaceutical composition contains PS at a concentration of 3% w / w or less of the pharmaceutical composition, for example, at a concentration of about 2% or about 1% w / w of the pharmaceutical composition, The pharmaceutical composition according to claim 10.

13. a) the PS is from about 0.005 g / 10 cm ２ of the affected area to about 0.25 g / 10 cm ２ of the affected area and is administered, optionally, the PS is I) About 0.005 g / 10 cm² of the affected area, II) About 0.01 g / 10 cm² of the affected area, III) About 0.05 g / 10 cm² of the affected area, IV) About 0.1 g / 10 cm² of the affected area, V) About 0.15 g / 10 cm² of the affected area, VI) About 0.2 g / 10 cm² of the affected area, or VII) About 0.25 g / 10 cm² of the affected area is administered; and / or b) The PS is applied to the affected area and left on the affected area for about 1 hour to about 5 hours, optionally, I) The PS is applied to the affected area and left on the affected area for about 0.5 hour, about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours, and / or II) A) After the administration period, the PS is removed from the affected area, for example, by flushing, or B) After the administration period, subsequent applications of the PS are applied to the affected area, The pharmaceutical composition according to claim 9.

14. a) The PS is applied once a day, b) The PS is applied twice a day, c) The PS is applied three times a day, d) The PS is applied four times a day, The pharmaceutical composition according to claim 9.

15. The pharmaceutical composition according to claim 13 or 14, wherein the PS is administered as a pharmaceutical composition.

Images