Phosphosulcln isomers

Abstract

The present invention relates to enantiomeric forms of sulindac phosphate, in particular S ) sulindac phosphate and compositions thereof, methods of preparation and use in methods of treatment.

Description

[0001] This application claims the benefits of U.S. Provisional Application No. 63 / 601366, filed November 21, 2023; U.S. Provisional Application No. 63 / 601362, filed November 21, 2023; U.S. Provisional Application No. 63 / 650558, filed May 22, 2024; and PCT Applications PCT / US2023 / 080646 and PCT / US2023 / 080649, filed November 21, 2023, the entire contents of which are incorporated herein by reference for all purposes. Technical Field

[0002] This invention relates to sulindac phosphate enantiomers and compositions thereof, methods for preparing sulindac phosphate enantiomers, and the use of sulindac phosphate enantiomers in treatment, such as in the treatment of dry eye syndrome. Background Technology

[0003] Dry eye syndrome (DED) is a common condition affecting about one in six people (15% of the population). It is estimated that more than 600 million people worldwide suffer from moderate to severe DED. Although there are many unrelated causes of DED, all of them share a common effect: the rupture of the tear film, leading to dehydration and subsequent damage to the exposed outer surface of the eye.

[0004] Treatment for DED includes palliative agents (such as artificial tear formulations) and active agents (such as corticosteroids, retinoic acid, oral pilocarpine, cyclosporine, and nonsteroidal anti-inflammatory drugs (NSAIDs)).

[0005] WO2009 / 023631 discloses sulindac phosphate, but not its optically active form. Sulindac phosphate is effective in a rabbit model of dry eye; see Examples 1-5 and 8 of WO2018 / 064354.

[0006] Treatment of DED still requires more effective active agents. Summary of the Invention

[0007] Sulinic acid phosphate contains a steric sulfur atom as part of its sulfoxide group, therefore it is a chiral molecule. The inventors unexpectedly discovered that... S )-Sullina phosphate, ( RSulindac phosphate and racemic sulindac phosphate, when applied topically, showed similar effects in a disease model of neuropathic pain associated with chemotherapy-induced peripheral neuropathy (see Example 3 in this paper and Basu, A. et al., Front Neurosci (2024); 17:1240372). While this finding suggests that each enantiomer of sulindac phosphate possesses therapeutic activity, the lack of differential effects observed between the enantiomers was unexpected.

[0008] In view of these results, the inventors hypothesize ( S )-Sullina phosphate and ( R Sulindac phosphate (SFP) provides the same efficacy in other disease models. However, the inventors also unexpectedly discovered that in a dry eye model, ( S )-Sullina phosphate ratio ( R Sulindac phosphate is more effective (see Example 4 of this document). These data support ( S Sulindac phosphate will provide enhanced efficacy in the treatment of DED.

[0009] Therefore, in one aspect, the present invention provides a compound having the following structure: (( S )-Sullina phosphate).

[0010] In one aspect, the present invention provides a product comprising ( S A composition of sullinic acid phosphate.

[0011] In one aspect, the present invention provides a method for preparing enantiomer-enriched ( ) by chromatography. S A method for separating sulindac phosphate enantiomers, the method comprising: a) separating a mixture containing sulindac phosphate enantiomers using a chiral stationary phase; and b) separating enantiomer-enriched ( S )-Sullina phosphate.

[0012] In one aspect, the present invention provides a treatment ( S )-Sullina phosphate. In one aspect, the present invention provides ( S Sulindac phosphate (SAP) is used to treat the diseases described herein, such as dry eye syndrome or neuropathic pain associated with chemotherapy-induced peripheral neuropathy (CIPN). In one aspect, the present invention provides a method of treating the diseases described herein (e.g., dry eye syndrome or neuropathic pain associated with CIPN), the method comprising administering to a patient a therapeutically effective amount of (SAP). S )-Sullina phosphate. In one aspect, the present invention provides ( SThe use of sulindac phosphate is for the manufacture of medicines for the treatment of the diseases described herein.

[0013] The embodiments described herein will also ( R Sulinic acid phosphate (SAP) has been identified as a compound that can be used for treatment. Therefore, in another aspect, the present invention provides a compound having the following structure: (( R )-Sullina phosphate)) In one aspect, the present invention provides a product comprising ( R A composition of sullinic acid phosphate.

[0014] In one aspect, the present invention provides a method for preparing enantiomer-enriched ( ) by chromatography. R A method for separating sulindac phosphate enantiomers, the method comprising: a) separating a mixture containing sulindac phosphate enantiomers using a chiral stationary phase; and b) separating enantiomer-enriched ( R )-Sullina phosphate.

[0015] In one aspect, the present invention provides a treatment ( R )-Sullina phosphate. In one aspect, the present invention provides ( R Sulindac phosphate (SAP) is used to treat the diseases described herein, such as dry eye syndrome or neuropathic pain associated with chemotherapy-induced peripheral neuropathy (CIPN). In one aspect, the present invention provides a method of treating the diseases described herein (e.g., dry eye syndrome or neuropathic pain associated with CIPN), the method comprising administering to a patient a therapeutically effective amount of (SAP). R )-Sullina phosphate. In one aspect, the present invention provides ( R The use of sulindac phosphate is for the manufacture of medicines for the treatment of the diseases described herein.

[0016] Furthermore, the inventors unexpectedly demonstrated that, when administered orally, ( S Sulindac phosphate is more effective than other phosphates in treating neuropathic pain associated with CIPN, post-traumatic peripheral neuropathy (PTPN), and migraine pain. R Sulindac phosphate is more effective. Therefore, in another aspect, the present invention provides a method for treating a disease in a patient in need, comprising administering to the patient a therapeutically effective amount of (sulindac phosphate). S )-Sullina phosphate, of which ( S Sulindac phosphate is administered orally. This invention also provides a treatment for (…). S )-Sullina phosphate, of which ( S Sulindac phosphate is administered orally.

[0017] On the other hand, the present invention provides a method for treating and / or preventing CIPN-related neuropathic pain in patients in need, the method comprising administering to the patient a therapeutically effective dose ( S )-Sullina phosphate, of which ( S Sulindac phosphate (SPF) is administered orally. In another aspect, the present invention provides a method for treating and / or preventing PTPN-related neuropathic pain in patients of need, the method comprising administering to the patient a therapeutically effective amount of (SPF). S )-Sullina phosphate, of which ( S Sulindac phosphate (SAP) is administered orally. In another aspect, the present invention provides a method for treating and / or preventing migraine pain in a patient in need, the method comprising administering to the patient a therapeutically effective amount of (SAP). S )-Sullina phosphate, of which ( S Sulindac phosphate (SPH) is administered orally. In another aspect, the present invention provides a method for treating and / or preventing neuropathic pain associated with central sensitization in patients in need, the method comprising administering to the patient a therapeutically effective amount of (SPH). S )-Sullina phosphate, of which ( S Sulindac phosphate is administered orally. Attached Figure Description

[0018] Figure 1A – Chromatogram of racemic sulindac phosphate; x-axis represents time (minutes), y-axis represents mAU (milliosorbates). The top line represents the absorbance at 220 nm, the middle line represents the absorbance at 254 nm, and the bottom line represents the absorbance at 280 nm. The area % of peak 1 is 49.833, and the area % of peak 2 is 50.167.

[0019] Figure 1B –Chromatogram of the enantiomer of sulindac phosphate, referred to as Peak 1 or Isomer 1; x-axis is time (minutes), y-axis is mAU. These lines show absorbance at 220 nm (top), 254 nm (middle), and 280 nm (bottom). The peak is at 1.91 min.

[0020] Figure 1C –Chromatogram of the enantiomer of sulindac phosphate, referred to as peak 2 or isomer 2; x-axis is time (minutes), y-axis is mAU. These lines show absorbance at 220 nm (top), 254 nm (middle), and 280 nm (bottom). The peak is at 2.58 min.

[0021] Figure 2A– Experimental infrared (IR) and vibrational circular dichroism (VCD) spectra of peak 2, and calculated IR and VCD spectra of compounds in model system 1. No frequency scaling factor was applied to these figures. Compounds in model system 1 (( R The calculated VCD spectra of the stereochemical compounds are shown in the lower right corner of the figure. S - VCD spectra of enantiomers (via inversion) R The signs of the peaks calculated from the enantiomers are obtained by superimposing them. Figure 2F The model system 1 compound (( R The calculated VCD spectrum of (-stereochemistry) is shown in the top line of the previous frame, without superimposed spectra of opposite enantiomers.

[0022] Figure 2B – Experimental IR and VCD spectra of peak 2 and calculated IR and VCD spectra of compounds in model system 1. Compounds in model system 2 (( R The calculated VCD spectra of the stereochemical compounds are shown in the lower right corner of the figure. S) -VCD spectra of enantiomers (via inversion) R The signs of the peaks calculated from the enantiomers are obtained by superimposing them. Figure 2G The model system 2 compounds (( R The calculated VCD spectrum of (-stereochemistry) is shown in the top line of the previous frame, without superimposed spectra of opposite enantiomers.

[0023] Figure 2C –IR (lower frame) and VCD (upper frame) spectra of peak 2 in CDCl3; 100 µm optical path cell with BaF2 window; 18 hours of collection for each enantiomer; instrument at 1400 cm⁻¹ -1 Optimization was performed. The IR spectrum after solvent subtraction and the VCD spectrum after enantiomer subtraction are shown. The top trace is the VCD noise spectrum.

[0024] Figure 2D –IR (lower frame) and VCD (upper frame) spectra of peak 1 in CDCl3; 100 µm optical path cell with BaF2 window; 18 hours of collection for each enantiomer; instrument at 1400 cm⁻¹ -1 Optimization was performed. The IR spectrum after solvent subtraction and the VCD spectrum after enantiomer subtraction are shown. The top trace is the VCD noise spectrum.

[0025] Figure 2E – The superposition of peaks 2 and 1 of the two enantiomers. The IR is almost identical, as expected. Due to the half-difference processing (E1 – E2) / 2, the VCD is mirrored.

[0026] Figure 2F – Peak 2 observed IR (lower frame) and VCD (upper frame) spectra (left axis) compared with those of compound in model system 1. R Comparison of Boltzmann-averaged spectra (right axis) of the calculated conformation of the (-sulfur) configuration. The top line in each frame (figure) is the calculated spectrum. The bottom line in each frame is the experimentally obtained spectrum of peak 2.

[0027] Figure 2G – Peak 2 observed IR (lower frame) and VCD (upper frame) spectra (left axis) compared with those of compound in model system 2. R- Comparison of Boltzmann-averaged spectra (right axis) of the calculated conformations of the sulfur configuration. The top line in each frame (figure) is the calculated spectrum, and the bottom line is the experimentally obtained spectrum of peak 2.

[0028] Figure 2H –Model System 1 (( R The four lowest energy conformational isomers of the )-configuration (from the Boltzmann average of 83 conformational isomers).

[0029] Figure 2I –Model System 2 (( R The four lowest energy conformational isomers of the )-configuration (from the 10 conformational isomers of the Boltzmann average).

[0030] Figure 2J – A graph showing the ESI (Early Similarity of Correct Enantiomers to Computed Values ​​minus the Similarity of Incorrect Enantiomers to Computed Values) and SNS (Overall Similarity of Correct Enantiomers to Computed Values) of the correctly assigned library, independently verified by other X-ray methods. The arrows pointing to the indicated "X" represent data points for peak 2 and model system 1. The upper right corner represents the strongest assignment, and the lower left corner represents the weakest assignment.

[0031] Figure 3 – Effects of isomer 1, isomer 2, racemic PS, and mediator on neuropathic pain associated with chemotherapy-induced peripheral neuropathy. Value: Mean ± SEM *, p<0.005 compared to the medium.

[0032] Figure 4 – A bar chart of corneal sensitivity (cm), osmotic pressure (mOsm / KgH2O), tear film breakup time (seconds), and corneal fluorescein staining (score) for entries Con A, mediator, isomer 1, and isomer 2. D5 and D7 refer to day 5 and day 7, respectively. Detailed Implementation

[0033] definition The term "therapeutic effective amount" refers to an amount of the compound or combination of compounds described herein sufficient to achieve the intended application, including but not limited to treating, preventing, improving, and / or alleviating symptoms of a disease. Therapeutic effective amounts may vary depending on the intended use (in vitro or in vivo) or the subject being treated and the disease condition (e.g., the subject's weight, age, and sex), the severity of the disease condition, the method of administration, etc., which can be readily determined by those skilled in the art.

[0034] As used herein, the terms “treat,” “treatment,” and / or “treating” can refer to the management of a disease, condition, or pathological disorder or its symptoms with the aim of curing, improving, stabilizing, and / or controlling said disease, condition, pathological disorder, or its symptoms. More specifically, regarding the control of a disease, condition, or pathological disorder, “control” can include the prevention of disease progression, as assessed by response to the methods described herein, where such response may be complete (e.g., disease remission) or partial (e.g., reduction or improvement of any symptoms associated with the disorder). The term “treatment” includes preventative (e.g., prophylactic) treatment and / or therapeutic treatment. In other words, the term “treatment” can include treatment and / or prevention.

[0035] "Pharmaceutical compositions" and their formulations are well known in the art. See Tovey (ed., 2018). Pharmaceutical Formulation: The Science and Technology of Dosage Forms; 2018, Remington The Science and Practice of Pharmacy (23rd edition, 2020) Handbook of Pharmaceutical Excipients (Sheskey, Cook and Cable, eds.; 8th edition 2016), all references are incorporated herein by reference in full.

[0036] "Pharmaceutical-acceptable excipients" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delay agents, as well as inert components included in pharmaceutical compositions. The uses of these pharmaceutically acceptable excipients for formulating active pharmaceutical ingredients are 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.

[0037] When referring to a number, the use of the term "about" is optional and can mean + / - 5%, + / - 2%, or + / - 1%.

[0038] The term "comprising" encompasses "including," "mainly composed of," and "consisting of." For example, the use of "mainly composed of" for a compound or composition implies the presence of specific other components that do not materially affect the essential characteristics of the compound or composition.

[0039] "Isomers" are different compounds having the same molecular formula. "Stereoisomers" are isomers that differ only in the spatial arrangement of their atoms, i.e., they have different stereochemical configurations. "Enantiomers" are a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. Where appropriate, the term "(±)" may be used to denote a racemic mixture. The absolute stereochemistry of enantiomers is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry of each chiral atom can be determined by (…). R )or( S The compound can also be designated as (+) or (-) depending on the direction (right-handed or left-handed) of the plane-polarized light it rotates at the sodium D-line wavelength. Right-handed rotation is positive or clockwise and is indicated by (+). Left-handed rotation is negative or counterclockwise and is indicated by (-).

[0040] The term "enantiomer excess" (ee) is a measurement of the purity of chiral substances. It reflects the degree to which the content of one enantiomer in a sample is higher than that of another. The ee for a racemic mixture is 0%, while the ee for a single, completely pure enantiomer is 100%. The ee for a sample containing 70% of one enantiomer and 30% of the other enantiomer is 40% (70% - 30%). The term "enantiomer ratio" (er) is another measurement of the purity of chiral substances. The er for a racemic mixture is 50:50, while the er for a single, completely pure enantiomer is 100:0. The er for a sample containing 70% of one enantiomer and 30% of the other enantiomer is 70:30. The enantiomer excess or ratio of a compound can be determined by a variety of methods known in the art, including but not limited to chromatography using a chiral support, optical rotation measurement using polarized light rotation, nuclear magnetic resonance spectroscopy using chiral shift reagents (including but not limited to chiral complexes containing lanthanides or Pirkle's reagent), or derivatization of the compound using a chiral compound (e.g., Mosher's acid) followed by chromatography or nuclear magnetic resonance spectroscopy. In some embodiments, the enantiomer excess is determined by chromatography, such as supercritical fluid chromatography or high-performance liquid chromatography.

[0041] The sulfoxide group is usually represented by the structural formula RS(=O)-R', where R and R' are organic groups. The sulfur atom has a lone pair of electrons, giving it a tetrahedral electron pair geometry and a trigonal pyramidal shape. The S=O bond in the sulfoxide group can be structurally represented as a single SO bond, where the oxygen atom carries a negative charge and the sulfur atom carries a positive charge.

[0042] The following definitions of pain types follow the definition 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. "Central sensitization" refers to an increased responsiveness of nociceptive neurons in the central nervous system to normal or subthreshold input. "Peripheral sensitization" refers to an increased responsiveness and decreased threshold of nociceptive neurons in the peripheral nervous system to stimuli in their receptive fields. The exact causes of central and peripheral sensitization in neuropathic pain differ from those in other forms of pain, such as inflammatory pain. "Abnormal pain" is pain caused by stimuli that would not normally cause pain. "Hyperalgesia" is exacerbated pain caused by stimuli that would normally cause pain. Pain associated with central sensitization can be systemic or occur in multiple parts of the body.

[0043] Neuropathic pain is caused by lesions or diseases of the somatosensory nervous system. Neuropathic pain is a clinical description (not a diagnosis) requiring a provable lesion or disease that meets established neurological diagnostic criteria. Patients with neuropathic pain may experience one or more sensations described as burning, throbbing, snapping, tingling, sharp, spasmodic, aching, numbness, or pricking. The term "somatosensory nervous system injury" is often used when diagnostic investigations (e.g., imaging, neurophysiology, biopsy, laboratory tests) reveal abnormalities or when there is obvious trauma. The term "somatosensory nervous system disorder" is often used when the underlying cause of the lesion is known (e.g., stroke, vasculitis, diabetes, genetic abnormality). Peripheral neuropathic pain is pain caused by lesions or diseases of the peripheral somatosensory nervous system. Central neuropathic pain is pain caused by lesions or diseases of the central somatosensory nervous system.

[0044] The following definitions of headache types follow the International Classification of Headache Disorders (ICHD) 3rd edition (ICHD-3). There are two main types of migraine: "migraine without aura," a clinical syndrome characterized by headaches with specific features and associated symptoms; and "migraine with aura," characterized by transient focal neurological symptoms that usually precede or sometimes accompany the headache. "Migraine without aura" (i.e., common migraine; simple migraine) is a recurrent headache syndrome characterized by attacks lasting 4–72 hours. This headache usually occurs unilaterally, is throbbing, moderate to severe in intensity, and is exacerbated by daily physical activity, often accompanied by nausea and / or photophobia and phonophobia. "Migraine with aura" (i.e., classic or classical migraine) involves recurrent attacks lasting several minutes, with unilateral, fully reversible visual, sensory, or other CNS symptoms, usually developing gradually, and often accompanied by headache and related migraine symptoms. "Episodic migraine" typically involves migraines / headaches occurring about 1-2 times per month. "Chronic migraine" is defined as headaches lasting 15 days or longer per month for more than three months, with at least 8 days per month exhibiting migraine-type headache characteristics.

[0045] Sulindac phosphate (PS) Sulindac phosphate is disclosed in WO2009 / 023631 (see paragraph

[00123] ). Sulindac phosphate is also known as PS, PS-I, or OXT-328. The chemical name of sulindac phosphate is: 4-((diethoxyphosphoryl)oxy)butyl-( Z )-2-(5-fluoro-2-methyl-1-(4-(methylsulfinyl)benzyl)-1 H (indene-3-yl)acetic acid ester. Sulinic acid phosphate has the following structure. The '-C2H5' part is an ethyl group, i.e., the '-CH2CH3' group.

[0046] enantiomers of PS The enantiomers of PS have been isolated in their pure enantiomeric form and their absolute stereochemical configurations have been assigned—see Examples 1 and 2 described herein.

[0047] Therefore, in one aspect, the present invention provides a compound having the following structure: .

[0048] The above structure is that of sulindac phosphate (SAP). S )-enantiomers, i.e. (S )-Sullina phosphate. In the examples, ( S The enantiomer of sulindac phosphate is referred to as peak 1 or isomer 1. The enantiomers of sulindac phosphate can be defined without reference to their absolute stereochemistry. For example, the retention time of the enantiomer of sulindac phosphate is about 1.8–2.0 min, such as about 1.91 min, and can be measured by supercritical fluid chromatography, for example using a chiral stationary phase based on amylose tris(3,5-dimethylphenylcarbamate), a mobile phase of about 40% methanol / CO2, a flow rate of about 3 mL / min, a pressure of about 100 bar, and optionally UV detection at about 220 nm.

[0049] In another aspect, the present invention provides a compound having the following structure: .

[0050] The above structure is that of sulindac phosphate (SAP). R )-enantiomers, i.e. ( R )-Sullina phosphate. In the examples, ( R The enantiomer of sulindac phosphate is referred to as peak 2 or isomer 2. The enantiomers of sulindac phosphate can be defined without reference to their absolute stereochemistry. For example, the retention time of the enantiomer of sulindac phosphate is about 2.5–2.7 minutes, such as about 2.58 minutes, and can be measured by supercritical fluid chromatography, for example using a chiral stationary phase based on amylose tris(3,5-dimethylphenylcarbamate), a mobile phase of about 40% methanol / CO2, a flow rate of about 3 mL / min, a pressure of about 100 bar, and optionally UV detection at about 220 nm.

[0051] ( S )-Sullina phosphate and ( R (+)-Sullinacid phosphate is an example of the compounds provided herein or of the present invention. The enantiomers of sulinacid phosphate can also be defined by the direction of rotation of the plane-polarized light, for example, clockwise or counterclockwise. Therefore, the enantiomer of sulinacid phosphate is (+)-sulinacid phosphate. Alternatively, the enantiomer of sulinacid phosphate is (-)-sulinacid phosphate.

[0052] Pharmaceutically acceptable form The compounds described herein are provided in pharmaceutically acceptable forms. Therefore, ( S Sulindac phosphate (SAP) is available in pharmaceutically acceptable forms. Additionally, ( R Sulindac phosphate may be available in pharmaceutically acceptable forms. Examples of pharmaceutically acceptable forms include solvates, derivatives, and / or prodrugs.

[0053] Solvents.As used herein, the term "solvent" refers to a compound that further comprises stoichiometric or nonstoichiometric amounts of solvent bound by noncovalent intermolecular forces. When the solvent is water, the solvate is a hydrate. Therefore, ( S Pharmaceutically acceptable forms of sulindac phosphate can be solvates, such as hydrates. Additionally, ( R Pharmaceutically acceptable forms of sulindac phosphate may be solvates, such as hydrates. A solvate may comprise at least one solvent molecule. Alternatively, a solvate may comprise fewer than one solvent molecule.

[0054] isotope. Isotopically labeled derivatives are compounds identical to the mixtures described herein, but with one or more atoms replaced by atoms of different atomic masses or mass numbers than those commonly found in nature. Therefore, pharmaceutically acceptable ( S The sullinic acid phosphate form can be an isotopically labeled derivative. Additionally, pharmaceutically acceptable ( R Sulinic acid phosphate can be in the form of isotopically labeled derivatives. Isotopically labeled derivatives may include one or more isotopes of hydrogen, carbon, oxygen, phosphorus, sulfur, and fluorine. For example, isotopically labeled derivatives may include one or more of the following isotopes: 2 H, 3 H, 13 C 14 C 18 O、 17 O、 31 P, 32 P, 35 S and 18 F. In particular, isotopically labeled derivatives may include 2 One or more isotopes of hydrogen (deuterium). In particular, isotope-labeled derivatives include... 3 One or more isotopes of H (tritium). In particular, isotope-labeled derivatives include... 14 One or more isotopes of C.

[0055] Derivatives and prodrugs. Derivatives of sulindac phosphate may include tautomers, such as enols or enol salts. Therefore, pharmaceutically acceptable ( S The )- sulindac phosphate form may include ( S Derivatives of sulindac phosphate, such as tautomers. Additionally, pharmaceutically acceptable (…). R The )- sulindac phosphate form may include ( R Derivatives of sulindac phosphate, such as tautomers. In some embodiments, the derivative is a metabolite. In some embodiments, it is pharmaceutically acceptable. SThe )-phosphate sulindac form is ( S )-Sulindac phosphate prodrug. In some implementations, pharmaceutically acceptable ( R The )-phosphate sulindac form is ( R )-Sullinacid prodrug.

[0056] The activities of the compounds presented in this article will be common to their pharmaceutically acceptable forms.

[0057] Composition The compounds provided herein may be included in compositions, such as pharmaceutical compositions. In one aspect, the present invention provides a composition comprising ( S A composition comprising sullinic acid phosphate. In another aspect, the present invention provides a composition comprising ( R Compositions containing sulindac phosphate enantiomers. Compositions comprising sulindac phosphate enantiomers may be enantiomerically enriched relative to those enantiomers. For example, the composition may consist primarily of sulindac phosphate enantiomers. This does not preclude the presence of other (non-sulindac phosphate) components in the composition. Determining the ratio of sulindac phosphate enantiomers present in the composition may also be useful. For example, the enantiomer excess of sulindac phosphate enantiomers may be at least: 50%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%; or about 100%. Compositions with high enantiomer enrichment are preferred. Thus, in some embodiments, the enantiomer excess of sulindac phosphate enantiomers is at least 80%, 90%, 96%, or 98%. In some embodiments, the enantiomer excess of sulindac phosphate enantiomers is at least 80%. In some embodiments, the enantiomer of sulindac phosphate is in excess by at least 90%. In some embodiments, the enantiomer of sulindac phosphate is in excess by at least 96%. In some embodiments, the enantiomer of sulindac phosphate is in excess by at least 98%. In some embodiments, the enantiomer of sulindac phosphate is in excess by at least 99%. In some embodiments, the enantiomer of sulindac phosphate is in excess by about 100%.

[0058] As described above, sulindac phosphate enantiomers can be used for treatment. Therefore, the compositions provided herein can be pharmaceutical compositions. Pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of the compounds provided herein (e.g., […]). S 1-Sullina phosphate or I-Sullina phosphate).

[0059] In some embodiments, the composition (e.g., a pharmaceutical composition) further comprises an excipient. When the composition is pharmaceutically acceptable, the excipient is a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients may comprise one or more of the following: carriers, diluents, fillers, aqueous solutions, organic solvents, solubilizers, and adjuvants.

[0060] The compounds described in this article can be used to treat conditions such as dry eye syndrome. In particular, ( S Sulindac phosphate (SPP) can be used to treat dry eye syndrome. Therefore, in some embodiments, the pharmaceutical compositions provided herein are formulated for topical application. Specifically, topical application can be the application of the drug to the eye or tissues surrounding the eye. In some embodiments, the tissues surrounding the eye are the eyelids.

[0061] The pharmaceutical compositions provided herein can be formulated according to their route of administration, such as topical application. In some embodiments, they contain enantiomers of sulindac phosphate (e.g., (…)). S Pharmaceutical compositions containing sulindac phosphate (SPF) can be formulated as semi-solids or liquids. Therefore, pharmaceutical compositions containing enantiomers of SPF can be formulated as solutions, creams, gels (e.g., hydrogels), lotions, ointments, foams, and / or sprays. In some embodiments, pharmaceutical compositions containing enantiomers of SPF are formulated as creams. In some embodiments, pharmaceutical compositions containing enantiomers of SPF are formulated as gels (e.g., hydrogels). In some embodiments, pharmaceutical compositions containing enantiomers of SPF are formulated as lotions. These compositions have different relative concentrations of oil and water, thereby giving the compositions different densities. Changing the density of the formulation is one way to control the exposure of the affected area to the pharmaceutical composition. For example, if the density of the formulation is low, it may require rubbing until it is absorbed, potentially shortening the exposure time. Alternatively, if the density of the formulation is high, it may be less easily absorbed, potentially prolonging the time the area is exposed to the pharmaceutical composition. Those skilled in the art know how to formulate topical pharmaceutical compositions to change the relative exposure of the area to the active pharmaceutical ingredient.

[0062] Pharmaceutical compositions suitable for topical application and suitable pharmaceutically acceptable excipients are well known in the art. Exemplary formulations for topical application are provided in WO 2019 / 067919, which is hereby incorporated by reference in its entirety.

[0063] Contains enantiomers of sulindac phosphate (e.g., ( SA pharmaceutical composition of sulindac phosphate may comprise an enantiomer of the pharmaceutical composition at a concentration of about 0.05% w / w to about 15% w / w, wherein the pharmaceutical composition is suitable for topical application. Therefore, the concentration of the sulindac phosphate enantiomer may be 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%, 0.5%, 0.2%, 0.1%, or 0.05% w / w. As an illustrative example, when formulated into a topical cream, the concentration of the sulindac phosphate enantiomer may be less than or equal to about 8% w / w of the pharmaceutical composition, for example, less than or equal to about 6% w / w of the pharmaceutical composition, and particularly less than or equal to about 3% w / w of the pharmaceutical composition. As another illustrative example, when formulated into a gel, the concentration of the sulindac phosphate enantiomer may be less than or equal to 8% w / w of the pharmaceutical composition, for example, less than or equal to 6% w / w of the pharmaceutical composition, and particularly less than or equal to 3% w / w of the pharmaceutical composition, for example, about 2% or about 1% w / w of the pharmaceutical composition. In certain formulations, such as when formulated into a hydrogel or ointment, the concentration of the sulindac phosphate enantiomer may be less than or equal to about 6% w / w of the pharmaceutical composition.

[0064] Contains enantiomers of sulindac phosphate (e.g., S The pharmaceutical composition of sulindac phosphate can be alternatively formulated for any other form of administration suitable for the treatment of dry eye. For example, the pharmaceutical composition can be formulated as eye drops.

[0065] Contains enantiomers of sulindac phosphate (e.g., ( S Pharmaceutical compositions containing sulindac phosphate can be alternatively formulated for parenteral administration, such as intravenous, intramuscular, or subcutaneous administration. In specific embodiments, the pharmaceutical composition comprises an enantiomer of sulindac phosphate (e.g., sulindac enantiomer). S A pharmaceutical composition of sullinic acid phosphate (SPH) is formulated for oral administration.

[0066] Orally administered enantiomers of sulindac phosphate (e.g., ( S Sulinic acid phosphate (SAP) can be formulated into liquid or solid dosage forms.

[0067] Orally administered liquid dosage forms include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.

[0068] Orally administered solid dosage forms include, but are not limited to, capsules, tablets, pills, powders, and granules. Solid dosage forms such as tablets, sugar-coated pills, capsules, pills, and granules can be formulated with a coating and shell, such as enteric coating, controlled-release coating, and other coatings well known in the field of pharmaceutical formulation. The solid dosage forms of capsules, tablets, and pills can allow the enantiomers of sulindac phosphate to be released, optionally in a delayed manner, only or preferentially, in a portion of the intestine (e.g., the stomach).

[0069] In some embodiments, the orally administered formulation contains one or more fillers, disintegrants, lubricants, flow aids, anti-adhesion agents, and / or antistatic agents.

[0070] Formulations suitable for oral administration may contain sulindac phosphate enantiomers at concentrations 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 (e.g., ...). S )-Sullina phosphate).

[0071] The compositions or pharmaceutical compositions described herein may be sterile. Methods for sterilizing compositions are known in the art, such as by steam or UV radiation.

[0072] Preparation / Analysis Methods PS enantiomers can be prepared and / or analyzed—see Example 1 described herein. Therefore, in one aspect, the present invention provides a method for preparing enantiomer-enriched (PS) S Methods for preparing enantiomer-enriched 1-phosphosulinic acid, such as by chromatography. In another aspect, the present invention provides a method for preparing enantiomer-enriched 1-phosphosulinic acid, such as by chromatography. The method may include: a) separating a mixture containing enantiomers of sulinic acid phosphate using a chiral stationary phase; and b) separating the enantiomer-enriched sulinic acid phosphate enantiomers.

[0073] In one aspect, the present invention provides a method for determining the enantiomer excess of sulindac phosphate enantiomers, for example by chromatography. The method may include: (a) separating a mixture containing sulindac phosphate enantiomers using a chiral stationary phase; and (b) determining the enantiomer excess of sulindac phosphate enantiomers. In some embodiments, the enantiomers are (… S 1-Sullina phosphate. In some embodiments, the enantiomer is 1-Sullina phosphate.

[0074] In the method described herein, the enantiomeric excess of the enantiomeric sulindac phosphate enantiomeric isomers enriched relative to the mixture can be increased. Therefore, the enantiomeric excess of the sulindac phosphate enantiomeric isomers can be at least: 50%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%; or about 100%. High enantiomeric enrichment is preferred. Therefore, the enantiomeric excess of the sulindac phosphate enantiomeric isomers can be at least: 80%, 90%, 96%, or 98%. In some embodiments, the enantiomeric excess of the sulindac phosphate enantiomeric isomers is at least 80%. In some embodiments, the enantiomeric excess of the sulindac phosphate enantiomeric isomers is at least 90%. In some embodiments, the enantiomeric excess of the sulindac phosphate enantiomeric isomers is at least 96%. In some embodiments, the enantiomeric excess of the sulindac phosphate enantiomeric isomers is at least 98%. In some embodiments, the enantiomer of sulindac phosphate is in excess of at least 99%. In some embodiments, the enantiomer of sulindac phosphate is in excess of about 100%.

[0075] Example 1 relies on supercritical fluid chromatography (SCLC) to separate sulindac phosphate enantiomers. Therefore, in the methods provided herein, the chromatography can be supercritical fluid chromatography. The supercritical fluid chromatography described herein can use a mobile phase comprising methanol and CO2. For example, the mobile phase can be 25-45% (w / w) methanol, with the remainder being CO2. The methods described herein can be carried out at a pressure of approximately 100 bar.

[0076] The methods described herein for preparing enantiomer-enriched sulindac phosphate enantiomers (e.g., preparative methods) tend to utilize larger chiral stationary phases, which may require increasing the flow rate of the mobile phase. Therefore, supercritical fluid chromatography for preparing enantiomer-enriched sulindac phosphate enantiomers can be carried out at flow rates of 50-70 mL / min, for example, about 60 mL / min. A mixed solution containing sulindac phosphate enantiomers can be used to load the enantiomers onto the chiral stationary phase. In some embodiments, an injection volume of about 2 mL of the mixture is used in a solution of about 20 mg / mL in a solvent (e.g., methanol).

[0077] Supercritical fluid chromatography (e.g., analytical methods) for determining the enantiomer excess of sulindac phosphate enantiomers is performed at a flow rate of 2–4 mL / min, for example, about 3 mL / min. This is because the chiral stationary phase may be small.

[0078] Instruments that detect compounds eluted from the stationary phase can aid in the separation of said compounds. Therefore, the chromatographic methods described herein may also include the detection of enantiomers using a UV detector. In some embodiments, the wavelength range of the UV detector is from about 200 nm to about 300 nm. In some embodiments, the wavelength of the UV detector is about 220 nm, 254 nm, and / or 280 nm.

[0079] In the method provided herein, the separation of each enantiomer can be achieved using a chiral stationary phase. For example, the chiral stationary phase can be silica gel coated with a polysaccharide. Polysaccharides are chiral compounds, therefore each enantiomer typically interacts differently with the polysaccharide coating, thereby altering the elution time of each enantiomer and thus achieving separation. The chiral stationary phase can also be a linear starch derivative coated on silica gel. Specifically, the linear starch derivative is linear starch-tris(3,5-dimethylphenylcarbamate).

[0080] As shown in Example 1, each sulinic acid phosphate enantiomer can be prepared in enantiomer-enriched form using chromatographic methods. Therefore, sulinic acid phosphate enantiomers can be obtained by the methods provided herein.

[0081] Treatment Sulindac phosphate can be used for a variety of therapeutic applications. WO2018 / 064354 discloses the efficacy of sulindac phosphate in a rabbit dry eye model (see, for example, Examples 1-8). WO2022 / 251805 discloses that sulindac phosphate is effective in treating neuropathic pain associated with chemotherapy-induced peripheral neuropathy (CIPN).

[0082] The compounds provided in this article (e.g., ( S )-Sullina phosphate and ( R Sulinic acid phosphate and its compositions have also proven surprisingly useful in treatment, for example for treating dry eye or neuropathic pain associated with chemotherapy-induced peripheral neuropathy (CIPN)—see, for example, Examples 3 and 4 described herein.

[0083] Therefore, in one aspect, the present invention provides enantiomers of sulindac phosphate for therapeutic purposes (e.g., ( S ()-Sullina phosphate) or combinations thereof. The present invention also provides an enantiomer of sullina phosphate (e.g., () S The present invention provides a method for treating neuropathic pain associated with chemotherapy-induced peripheral neuropathy (CIPN) using sulindac phosphate (e.g., sulindac phosphate enantiomers) for treating dry eye syndrome. S The present invention also provides a composition comprising an enantiomer of sulinic acid phosphate (e.g., (sulinic acid phosphate)). SSulindac phosphate (SPH) is a method for treating the conditions described herein, such as dry eye syndrome or neuropathic pain associated with CIPN. In some embodiments, the enantiomer of SPH is ( S )-Sullina phosphate. In some embodiments, the enantiomer of sullina phosphate is ( R )-Sullina phosphate.

[0084] The present invention also provides a method for treating a disease in a patient in need, the method comprising administering to the patient a therapeutically effective amount of a sulindac phosphate enantiomer (e.g., ...). S (Sullina phosphate) or a combination thereof. The present invention also provides a method for treating dry eye in patients in need, the method comprising administering to the patient a therapeutically effective amount of a sulina phosphate enantiomer (e.g., (Sullina phosphate) enantiomer). S The present invention also provides a method for treating CIPN-related neuropathic pain in patients in need, the method comprising administering to the patient a therapeutically effective amount of a sulindac phosphate enantiomer (e.g., sulindac phosphate). S The present invention also provides a method for treating the diseases described herein (e.g., dry eye syndrome or neuropathic pain associated with CIPN), the method comprising administering to a patient a therapeutically effective amount of an enantiomer comprising sulina phosphate (e.g., sulina phosphate). S A composition of sulindac phosphate. In some embodiments, the enantiomer of sulindac phosphate is ( S )-Sullina phosphate. In some embodiments, the enantiomer of sullina phosphate is ( R )-Sullina phosphate.

[0085] The present invention also provides enantiomers of sulindac phosphate (e.g., ( S The invention provides the use of sulindac phosphate (SLP) or combinations thereof for the manufacture of medicaments for treating diseases. The invention also provides enantiomers of sulindac phosphate (e.g., (SLP)). S The invention also provides the use of sulindac phosphate (SLP) in the manufacture of medicaments for treating dry eye syndrome. The invention further provides enantiomers of SLP (e.g., sulindac phosphate enantiomers). S The invention provides the use of sulindac phosphate (SPF) in the manufacture of a medicament for treating neuropathic pain associated with CIPN. The invention also provides for the inclusion of enantiomers of sulindac phosphate (e.g., (…) S The use of a composition of sulindac phosphate for the manufacture of a medicament for the treatment of the diseases described herein, such as dry eye syndrome or neuropathic pain associated with CIPN. In some embodiments, the enantiomer of sulindac phosphate is ( S )-Sullina phosphate; in other embodiments, the enantiomer of sullina phosphate is ( R)-Sullina phosphate.

[0086] In some implementation schemes, the treatment (e.g., using ( S )-Sullina phosphate or containing ( S The diseases for which the sulindac-phosphate composition is selected are one or more of the following: pain associated with central sensitization (e.g., inflammatory pain; neuropathic pain; fibromyalgia; chronic pain; chronic regional pain syndrome; rheumatoid arthritis; psoriatic arthritis; osteoarthritis; spondyloarthritis; lupus; temporomandibular joint disorder; and / or idiopathic low back pain); neuropathic pain associated with diabetic peripheral neuropathy (DPN); neuropathic pain associated with post-traumatic peripheral neuropathy (PTPN); neuropathic pain associated with postherpetic neuropathy (PHN); migraine pain (or pain associated with other headache conditions); and corneal neuropathic pain. In some embodiments, the pain associated with central sensitization is not caused by chemotherapy-induced peripheral neuropathy (CIPN).

[0087] Pain may result from central sensitization leading to atypical pain (such as mechanical atypical pain) and / or hyperalgesia. Sulindac phosphate enantiomers (e.g., ( S Sulinacid phosphate (SPH) can reduce neuronal signaling involved in pain perception in subjects. Sulinacid phosphate enantiomers (e.g., […]) S Sulindac phosphate (SPH) can alleviate pain caused by central sensitization. In some cases, the relief can be complete, thereby eliminating the pain. Therefore, enantiomers of SPH (e.g., (SPH)) can be used to reduce pain caused by central sensitization. S Sulina phosphate (SPH) can reduce the transmission of pain signals in the central nervous system. For example, as disclosed herein, enantiomers of SPH (e.g., sulina phosphate) S Sulindac phosphate (SPF) can reduce pain production in central neurons, such as neurons in one or more areas of the brain that are associated with pain generation and / or sensation.

[0088] In a specific embodiment, the disease to be treated is neuropathic pain associated with CIPN. In a specific embodiment, the disease to be treated is neuropathic pain associated with PTPN. In another preferred embodiment, the disease to be treated is migraine pain. In such embodiments, the enantiomers of sulindac phosphate, particularly ( S Sulinic acid phosphate (SAP) can be administered orally.

[0089] Neuropathic pain associated with CIPN may result from central sensitization leading to atypical pain (such as mechanical atypical pain) and / or hyperalgesia. Sulindac phosphate enantiomers (e.g., ( SSulinacid phosphate (SPH) can reduce neuronal signaling involved in pain perception in subjects receiving or following chemotherapy. Sulinacid phosphate enantiomers (e.g., […]) S Sulindac phosphate (SPH) can alleviate pain caused by central sensitization. In some cases, the relief can be complete, thereby eliminating the pain. Therefore, enantiomers of SPH (e.g., (SPH)) can be used to reduce pain caused by central sensitization. S Sulina phosphate (SPH) can reduce the transmission of pain signals in the central nervous system. For example, as disclosed herein, enantiomers of SPH (e.g., sulina phosphate) S Sulindac phosphate (SPF) can reduce pain production in central neurons, such as neurons in one or more areas of the brain that are associated with pain generation and / or sensation.

[0090] Neuropathic pain associated with PTPN may result from central sensitization leading to atypical pain (such as mechanical atypical pain) and / or hyperalgesia. Sulindac phosphate enantiomers (e.g., (…) S Sulinacid phosphate (SPF) can reduce neuronal signaling involved in pain perception in PTPN subjects. Sulinacid phosphate enantiomers (e.g., ...) S Sulindac phosphate (SPH) can alleviate pain caused by central sensitization. In some cases, the relief can be complete, thereby eliminating the pain. Therefore, enantiomers of SPH (e.g., (SPH)) can be used to reduce pain caused by central sensitization. S Sulina phosphate (SPH) can reduce the transmission of pain signals in the central nervous system. For example, as disclosed herein, enantiomers of SPH (e.g., sulina phosphate) S Sulindac phosphate (SPF) can reduce pain production in central neurons, such as neurons in one or more areas of the brain that are associated with pain generation and / or sensation.

[0091] Migraine can be episodic. In some cases, migraine can be chronic. Migraine can be migraine without aura or migraine with aura. Migraine with aura can be typical migraine with aura or brainstem migraine with aura. Migraine can be hemiplegic migraine (e.g., familial hemiplegic migraine or sporadic hemiplegic migraine); retinal migraine; chronic migraine; or probabilistic migraine (with and without aura). Migraine pain may be a result of central sensitization leading to atypical pain, such as atypical cutaneous pain and / or hyperalgesia. Sulindac phosphate enantiomers (e.g., ( S Sulindac phosphate (SPF) can reduce neuronal signaling involved in pain perception in migraine sufferers. In some cases, this reduction can be complete, thereby eliminating pain. Furthermore, enantiomers of SPF (e.g., sulindac phosphate) can also be used. S Sulindac phosphate (SPH) can alleviate pain caused by central sensitization. This alleviation can be complete, thereby eliminating the generation of pain. Therefore, enantiomers of SPH (e.g., sulindac phosphate)S Sulindac phosphate (SPF) can reduce the transmission of pain signals in the central nervous system. In some embodiments, the pain is atypical pain, such as atypical cutaneous pain. Atypical pain may be a response to mechanical and / or thermal stimuli. Furthermore, in some embodiments, the pain is hyperalgesia. Migraine pain can be neuropathic pain.

[0092] Migraine sufferers can be diagnosed using the well-known ICHD-3 guidelines. Migraine pain can be measured using the Visual Analogue Scale or any other appropriate method in the field.

[0093] The methods described herein may include administering a therapeutically effective amount of a sulindac phosphate enantiomer to a patient. In such methods, the therapeutically effective amount of the sulindac phosphate enantiomer is typically not administered in the form of racemic sulindac phosphate.

[0094] In treating the diseases described herein, sulindac phosphate enantiomers can be applied topically, for example, to the eye or tissues surrounding the eye, such as the eyelids. In some embodiments, sulindac phosphate enantiomers are applied topically to the outer surface of one or more eyelids. The one or more eyelids may be one or both upper eyelids and / or one or both lower eyelids. Sulindac phosphate enantiomers (e.g., (…) S Sulindac phosphate (SAP) can be administered parenterally, such as intravenously, intramuscularly, or subcutaneously.

[0095] In a specific implementation scheme, the enantiomers of sulinac phosphate (e.g., (…) S Sulindac phosphate (SPH) is administered orally. In some embodiments, the enantiomer of SPH (e.g., sulindac phosphate) is administered orally. S Sulindac phosphate (SLP) reduces pain signal transduction in the brain. When administered orally, SLP enantiomers (e.g., sullindac phosphate) reduce pain signal transduction in the brain. S Sulindac phosphate can accumulate at therapeutically relevant levels (via the vagus nerve) in the primary somatosensory cortex, secondary somatosensory cortex, anterior cingulate cortex (ACC), prefrontal cortex (PFC), insular cortex, amygdala, thalamus, cerebellum, and periaqueductal gray matter (PAG) of the midbrain. In a specific embodiment, when administered orally, sulindac phosphate enantiomers (e.g., (…)) can be used to treat the primary somatosensory cortex, secondary somatosensory cortex, anterior cingulate cortex (ACC), prefrontal cortex (PFC), insular cortex, amygdala, thalamus, cerebellum, and periaqueductal gray matter (PAG) of the midbrain. S Sulindac phosphate accumulates in the medulla oblongata and / or cerebellum at therapeutically relevant levels. For example, when administered orally, sulindac phosphate enantiomers (e.g., sulindac enantiomers) accumulate at therapeutically relevant levels. S Sulindac phosphate (SLP) can reduce pain signal transduction in somatosensory cortex, such as the primary somatosensory cortex. Orally administered enantiomers of SLP (e.g., sulindac phosphate) SSulindac phosphate (SPF) can reduce pain signal transduction in one or more of the following brain regions: primary somatosensory cortex, secondary somatosensory cortex, anterior cingulate cortex, prefrontal cortex, insular cortex, amygdala, thalamus, cerebellum, and periaqueductal gray matter of the midbrain. In a specific implementation, an orally administered enantiomer of SPF (e.g., sulindac phosphate) S Sulindac phosphate (SPF) can reduce pain signal transduction in the medulla oblongata and / or cerebellum.

[0096] Sulinic acid phosphate enantiomers (e.g., ( S The oral dose levels of sulindac phosphate can be from about 0.01 mg / kg to about 100 mg / kg, from about 0.05 mg / kg to about 50 mg / kg, or from about 0.1 mg / kg to about 10 mg / kg of the subject's body weight. In a specific implementation, the enantiomers of sulindac phosphate (e.g., (…)) S The dosage level of sulindac phosphate can be from about 1 mg / kg to about 5 mg / kg of subject weight, for example, about 3 mg / kg of subject weight.

[0097] Sulinic acid phosphate enantiomers (e.g., ( S The oral dose of sulindac phosphate can be from about 1 mg to about 2000 mg. In some embodiments, the enantiomer of sulindac phosphate (e.g., (…)) S The oral dose of sulindac phosphate can be from about 100 mg to 1500 mg, for example, from about 200 mg to about 1000 mg. In some embodiments, the enantiomer of sulindac phosphate (e.g., ( S The oral dose of sulindac phosphate can be from about 50 mg to about 400 mg, for example from about 100 mg to about 350 mg, for example from about 150 mg to about 300 mg, for example from about 150 mg to about 250 mg. In a specific embodiment, the enantiomer of sulindac phosphate (e.g., ( S The oral dose of sulindac phosphate is from about 250 mg to about 300 mg, preferably about 250 mg. In some embodiments with multiple dosing, an equal amount of sulindac phosphate enantiomer (e.g., ...) may be administered with each dose. S (Sullina phosphate). In other embodiments, a higher initial dose may be administered, followed by a lower maintenance dose.

[0098] In some implementations, sulindac phosphate enantiomers (e.g., ( S Sulindac phosphate (SPH) can be administered orally once daily or more frequently. For example, it can be administered twice daily, three times daily, four times daily, or more frequently as needed. The enantiomers of sulindac phosphate (e.g., ...) can be administered as follows:S )-Sullina phosphate). In a specific implementation plan, the enantiomer of sullina phosphate (e.g., ( S )-Sullina phosphate).

[0099] In a specific implementation scheme, the enantiomers of sulinac phosphate (e.g., (…) S The oral dose of sulindac phosphate is approximately 150 mg to approximately 200 mg twice daily. Therefore, subjects may be given an oral dose of approximately 300 mg to approximately 400 mg of the enantiomer of sulindac phosphate (e.g., sulindac enantiomer). S )-Sullina phosphate).

[0100] In a specific implementation scheme, the enantiomers of sulinac phosphate (e.g., (…) S The oral dose of sulindac phosphate is about 250 mg to about 300 mg (e.g., about 250 mg) twice or three times daily. Therefore, subjects may be given daily doses of about 500 mg to up to about 900 mg of the enantiomer of sulindac phosphate (e.g., sulindac enantiomer). S (Sullinic acid phosphate), for example, PS.

[0101] The duration of continuous administration of sulindac phosphate enantiomers. In some embodiments, sulindac phosphate enantiomers are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, 28, 56, or 84 days. In some embodiments, sulindac phosphate enantiomers are continuously administered long-term to treat chronic effects, such as for at least 3 months. In some embodiments, continuous administration and maintenance are achieved for the required duration. In some embodiments, sulindac phosphate enantiomers are administered intermittently based on the recurrence of symptoms of the disease described herein (e.g., dry eye).

[0102] Sulindac phosphate enantiomers can be administered multiple times daily. In particular, sulindac phosphate enantiomers can be administered once, twice, three, four, five, or six times daily, or multiple times within 24 hours as needed.

[0103] The application of sulindac phosphate enantiomers can be performed multiple times a day and can be continued as needed, as described in the paragraphs above.

[0104] Those skilled in the art will understand that, in some embodiments, the dosage of these compounds can be adjusted according to the mammal to be treated. For example, treatment of mice is described herein, and administration of sulindac phosphate enantiomers (e.g., ...) to humans... SThe dosage of sulindac phosphate may or may not be modified. However, those skilled in the art may adapt the dosages provided herein as needed, as described in the Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers (published in July 2005 by the Center for Drug Evaluation and Research (CDER) of the U.S. Department of Health and Human Services, Food and Drug Administration). Human equivalent dose (HED) can be determined from animal doses, which can be multiplied by the following conversion factors to provide units of 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, miniature pig = 0.73, and small pig = 0.95.

[0105] The patient in the method described herein can be a mammal. In a preferred embodiment, the patient is a human.

[0106] Example The embodiments covered herein will now be described with reference to the following examples. These examples are provided for illustrative purposes only, and the disclosure covered herein should not in any way be construed as limiting to these examples, but rather as covering any and all variations that become apparent as a result of the teachings provided herein.

[0107] Example 1: Separation of racemic sulindac phosphate enantiomers by SFC Sulindac phosphate is disclosed in WO2009 / 023631 (paragraph

[123] ). Sulindac phosphate can be analyzed by the following analytical method: using a CHIRALPAK® AD-H (25 × 0.46 cm) column as the chiral stationary phase, a mobile phase of 40% methanol / CO2 (100 bar), a flow rate of 3 mL / min, and UV detection wavelengths of 220, 254 and 280 nm. Figure 1AThis is a chromatogram of racemic sulindac phosphate, showing the separation of enantiomers. The CHIRALPAK® AD-H column, manufactured by Daicel Corporation (Japan), is a chiral column containing silica gel coated with amylose tris(3,5-dimethylphenylcarbamate). Separation of each enantiomer was achieved through peaks at retention times of 1.91 min and 2.58 min.

[0108] The enantiomers of racemic sulindac phosphate were separated by preparative supercritical fluid chromatography (SFC) using the following method: a CHIRALPAK® AD-H (25 × 3 cm) column was used as the chiral stationary phase, with a mobile phase of 30% methanol / CO2 (100 bar), a flow rate of 60 mL / min, and a UV detection wavelength of 220 nm. The injection volume was 2 mL (a 20 mg / mL solution of racemic sulindac phosphate in methanol). In a typical preparative SFC run, 7 g of sulindac phosphate produced approximately 3.6 g of isomer 1 (peak 1) and approximately 3.4 g of isomer 2 (peak 2). The slight difference in the yields of the two isomers may be due to residual solvent in the isomer 1 sample. Figure 1B This is the chromatogram of the sample containing sulindac phosphate isomer 1 (enantiomer), with a retention time of 1.91 minutes. Figure 1C This is the chromatogram of the sample containing sulindac phosphate isomer 2 (another enantiomer), with a retention time of 2.58 minutes. Figure 1B and 1C In the chromatograms, no opposite enantiomers were detected. Therefore, the preparative SFC method provides each sulinic acid phosphate enantiomer in its pure enantiomer form.

[0109] Example 2: Determining the absolute configuration by vibrational circular dichroism (VCD) method For an overview of the methods, see Kellenbach et al. Spectroscopy Europe / World Volume 19, Issue 4 (2007), pp. 15-18. Determining the absolute configuration via VCD involves the following steps: Experimental infrared (IR) and VCD spectra of each sulinic acid phosphate enantiomer were measured. The IR and VCD spectra of model systems 1 and 2 (structures below) enantiomers were simulated using ab initio density functional theory (DFT). The experimental and calculated spectra were then compared to determine which enantiomer best correlated with the model system of known absolute configuration.

[0110] result: Table 1: Measurement parameters of the spectra obtained in the experiment:

[0111] Table 2: Calculation details of the spectrum:

[0112] Table 3: Model systems for calculating spectra:

[0113] Table 4: Numerical comparison describes the IR and VCD spectra of the (R-sulfur) enantiomers calculated at the 6–31 G(d) / B3PW91 w / CPCM (chloroform) level and the observed IR and VCD spectra of peak 2 in the 945–1900 cm⁻¹ range. -1 Similarity within the range:

[0114] a Σ: Single VCD similarity, giving the similarity between the calculated VCD spectrum and the observed VCD spectrum. b Δ: Enantiomer similarity index, which gives the difference between the Σ values ​​of two enantiomers of a given diastereomer.

[0115] Confidence level is a measure of the degree of agreement between the calculated and measured spectra. A confidence level of 100% is given if the same spectra are being compared. Confidence level (CL) is not the probability of a correct assignment, but rather a measure of the quality or degree of agreement between the calculated and measured spectra. This molecule has a CL of 99%, indicating excellent visual agreement between the measured and calculated spectra—a very high confidence level assignment. The high flexibility of the molecule necessitates the use of a model system to ensure a reasonable number of conformations are available for calculation. Two different systems were calculated. The first system (Model System 1) has a structure closer to the actual molecule, with 610 initial calculated conformations, and is limited to the small basis set 6-31G(d). The second model system (Model System 2) is a more radical truncation with only 10 conformational isomers, allowing the use of the larger basis set 6-311G(3df, 2pd) and cc-pVTZ. For VCDs, these are reasonable approximations because the chiral sulfoxide center is always located at one end of the molecule—atoms far from the chirality contribute very little to the VCD signal—especially because they are separated by long methylene chains. Results for two model systems are presented and show excellent agreement with experimental data.

[0116] Figure 2A The experimental and calculated IR and VCD results for peak 2 and model system 1 are shown. In particular, the calculated IR and VCD spectra are predicted very well. The VCD spectrum of experimentally obtained peak 2 is compared with the calculated VCD spectrum of compound 1 (at the sulfur atom). RThe configuration is consistent with that of peak 2, supporting the absolute stereochemistry of the sulfur atom. R Generally, any superimposed (R) and (S) VCD spectra can be interpreted by referring to the VCD spectra of a single enantiomer, since the (R) and (S) VCD spectra are approximately mirror images of each other (e.g., see...). Figure 2C -E).

[0117] Figure 2B Experimental and calculated IR and VCD results for peak 2 and model system 2 are shown. Although the calculated IR spectrum prediction is poor due to the lack of phosphate stretching vibrations, the calculated VCD spectrum prediction is very good. The experimentally obtained VCD spectrum of peak 2 is compared with the calculated VCD spectrum of the compound in model system 2 (at the sulfur atom). R The configuration is consistent with the absolute stereochemistry of the sulfur atom at peak 2. R ).

[0118] Figure 2C and 2D The experimental IR and VCD spectra of peak 1 and peak 2 are shown respectively. The VCD spectrum of peak 1 appears to be a mirror image of the VCD spectrum of peak 2. The VCD spectra of peak 1 and peak 2 are... Figure 2E The superposition in the top frame further proves the mirror symmetry.

[0119] Figure 2F The peak 2 and compound 1 of model system were compared. R Experimental and calculated IR and VCD spectra of the ))-configuration). The figure above shows the VCD spectrum, with the top line representing the calculated VCD spectrum and the bottom line representing the experimental VCD spectrum. The consistent sign and amplitude of the VCD spectra indicate that peak 2 is the () of sulindac phosphate. R - Enantiomers. The figure below shows the IR spectra, with the top line representing the calculated IR spectrum and the bottom line representing the experimental IR spectrum.

[0120] Figure 2G The peak 2 and model system 2 compounds were compared. R Experimental and calculated IR and VCD spectra of the ))-configuration). The figure above shows the VCD spectrum, with the top line representing the calculated VCD spectrum and the bottom line representing the experimental VCD spectrum. The consistent sign and amplitude of the VCD spectra indicate that peak 2 is the () of sulindac phosphate. R - Enantiomers. The figure below shows the IR spectra, with the top line representing the calculated IR spectrum and the bottom line representing the experimental IR spectrum.

[0121] Figure 2H The calculations for the four lowest-energy conformational isomers of the compounds in Model System 1 are shown. Figure 2I The calculations for the four lowest-energy conformational isomers of the compounds in Model System 2 are shown. Figure 2JThis further demonstrates that the absolute stereochemistry of the enantiomers of sulinic acid phosphate has been fully determined.

[0122] in conclusion The absolute configuration of peak 1 is at the sulfur atom ( S (Confidence level: 99%). Therefore, isomer 1 (peak 1) is ( S )-Shulinic acid phosphate. The absolute configuration of peak 2 is ( ) at the sulfur atom. R (Confidence level: 99%). Therefore, isomer 2 (peak 2) is ( R )-Sullina phosphate.

[0123] Example 3: Efficacy of local application of racemic PS and its enantiomers in treating neuropathic pain in a CIPN mouse model Examples 1-4 of WO2022 / 251805 support the claim that PS can effectively treat and / or prevent neuropathic pain associated with chemotherapy-induced neuropathy.

[0124] In this embodiment, the treatment of neuropathic pain with enantiomers of PS when applied topically in a CIPN mouse model was evaluated.

[0125] method CIPN induction: CIPN was induced in mice using established protocols with paclitaxel (Carozzi et al., ExpNeurol (2010); 226:301-309; Currie et al., PLoS Biol (2019); 17:e3000243; Eldridge et al., Toxicol Pathol (2020); 48:190-201).

[0126] Paclitaxel was dissolved in a mixture of 1 volume of ethanol / 1 volume of Cremophor EL / 18 volumes of distilled water. Paclitaxel was administered via four intraperitoneal injections of 8 mg / kg paclitaxel (1 ml / 100 g body weight) every other day, for a cumulative dose of 32 mg / kg.

[0127] animal:Adult male C57BL / 6J mice, 8 weeks old and weighing 20-30 g at the start of the experiment, were purchased from Jackson Laboratory. Mice were housed in groups of four in an AAALAC-certified facility with free access to food and water. Mice in each cage were randomly assigned to treatment groups. All studies were conducted by researchers unaware of the treatment group identities. Experiments were conducted during the light cycle (7:00 AM to 7:00 PM), and animals were euthanized by CO2 asphyxiation. The study was approved by the Institutional Animal Care and Use Committee and followed the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. Animal research reports were submitted in accordance with ARRIVE guidelines.

[0128] ointment: Prepare a 5% ointment from racemic sulindac phosphate isomer 1 or isomer 2 for topical application.

[0129] Treatment options for diagnosed CIPN-related neuropathic pain: Once CIPN was confirmed by lowering the mechanical abnormal pain threshold, 5% racemic PS, isomer 1, or isomer 2 ointment or mordant ointment was applied to the hind paws of mice three times daily for 12 days. Mechanical abnormal pain was measured at the time points recorded in the figure (i.e., day 0 and day 12).

[0130] Mechanical abnormal pain assessment (von Frey test): Following established methods, the mechanical aberration pain threshold was determined using von Frey filaments (Chaplan et al., J Neurosci Methods (1994); 53:55-63; Bagdas et al., Biochem Pharmacol (2015); 97:590-600). Briefly, mice were placed in a quiet room for 30 minutes, then placed in a Plexiglas cage with a mesh metal floor for 30 minutes to acclimatize before testing. A series of calibrated von Frey filaments with increasing stiffness were applied vertically to the paw, with a force sufficient to cause a slight bend in the filament, held for 2-3 seconds. This process was repeated 5 times at each stiffness level, with several seconds between each bend. Paw retraction, licking, or shaking were all considered positive responses. The mechanical threshold, expressed in g, represents the force required to elicit a response from the animal to the von Frey filament.

[0131] Statistical analysis:Results are expressed as mean ± SEM. PK parameters were calculated using Microsoft Excel and PKSolver. Non-compartmental analysis was performed. Analysis of variance (ANOVA) was performed, followed by Bonferroni post-hoc tests. A difference was considered statistically significant when p < 0.05.

[0132] result The effects of racemic PS, isomer 1, and isomer 2 on paclitaxel-associated neuropathic pain in mice compared to the mediator were evaluated. This reflects a clinical scenario where patients experience neuropathic pain after initiating or completing chemotherapy.

[0133] like Figure 3 As shown, paclitaxel induced significant neuropathic pain, as evidenced by changes in mechanical abnormal pain. Following a diagnosis of neuropathic pain, topical treatment with enantiomers or PS in 5% gel form was initiated three times daily for 12 days.

[0134] Administration of paclitaxel to the study group significantly reduced their mechanical abnormal pain scores (mean 56%; range: 51%–61%), indicating neuropathic pain associated with CIPN.

[0135] Treatment with either enantiomer within 12 days after CIPN induction resulted in similar increases in atypical pain scores: Isomer 1: Day 0 = 1.13 ± 0.14 g vs. Day 12 = 1.64 ± 0.09 g (p < 0.005); and Isomer 2: Day 0 = 0.96 ± 0.07 g vs. Day 12 = 1.56 ± 0.18 g (p < 0.001). Racemic PS 5% gel showed similar effects: Day 0 = 1.04 ± 0.09 g vs. Day 12 = 1.59 ± 0.19 g (p < 0.005). Each of these effects was statistically different from the corresponding median value on Day 12 by 0.88 ± 0.08 g (p < 0.005 to 0.001), indicating that the enantiomers were equally effective for atypical pain compared to the racemic PS. These results are presented in… Figure 3 middle.

[0136] The safety of PS and its enantiomers. No local or systemic side effects were observed during all study periods when PS or its enantiomer ointment was applied to the hind paws of mice three times daily. This finding is consistent with the known safety profile of PS.

[0137] in conclusion Compared to paclitaxel-induced peripheral neuropathy (CIPN) scores, local application of racemic PS, isomer 1, and isomer 2 significantly improved CIPN scores. Therefore, both racemic PS and its two enantiomers treat CIPN-related neuropathic pain. Consistent with the results of Examples 1-4 of WO2022 / 251805, PS and each of its enantiomers demonstrated analgesic effects in a CIPN-related neuropathic pain treatment model. However, unexpectedly, each enantiomer and the racemic mixture of PS showed identical effects in the model. These results suggest that each enantiomer of PS is at least therapeutically useful, particularly when treating chemotherapy-induced peripheral neuropathy (CIPN)-related neuropathic pain.

[0138] Example 4: Effects of each enantiomer of PS on corneal sensitivity and dry eye (DED) PS is effective in the DED rabbit model (see WO2018 / 064354). In this embodiment, DED was induced by injecting concanavalin A (Con A) into the lacrimal glands around the orbit of male Netherland Dwarf rabbits, and the efficacy of each enantiomer of PS for corneal sensitivity and DED parameters was determined (see: Hondan et al. Transl Res 2018;198:58-72).

[0139] method Con A induced acute aqueous-deficient dry eye (DED). Male Dutch Black-banded rabbits (DB) weighing approximately 2 kg were used in this study. Two weeks after nictitating membrane excision, baseline values ​​for tear film breakup time (TBUT) and Schirmer tear test (STT) were obtained. The following day, dry eye was induced by ultrasound-guided injection of Con A dissolved in PBS into all lacrimal glands of the rabbits under deep isoflurane anesthesia. Bilateral injections were performed into the upper lacrimal gland (1,000 μg Con A, 0.2 mL) and orbital gland (500 μg Con A, 0.1 mL), and the lower lacrimal gland (1,000 μg Con A, 0.2 mL). Successful lower lacrimal gland injection was confirmed immediately post-injection by ultrasound. TBUT and STT were reassessed on day 5 post-Con A injection, confirming the induction of dry eye. Each of these parameters was measured 16 hours after the last dose of PS or isoform 1 or isoform 2.

[0140] The effectiveness of each enantiomer of PS was evaluated by measuring the following parameters attributed to DED: tear osmolarity, tear film breakup time (TBUT), and corneal fluorescein staining (CFS). Tear osmolarity and TBUT reflect tear quality, while CFS reflects ocular surface structural integrity.

[0141] Tear film breakup time (TBUT). After local anesthesia and placement of a wire eyelid speculum, 50 μL of 0.2% fluorescein eye drops are evenly instilled onto the eye, and the anterior corneal tear film is observed under blue light using a surgical magnifying glass. The time required for the appearance of black spots, lines, or obvious breakup of the fluorescein film is measured within a maximum of 1 minute. If no breakup is observed within 1 minute, observation is stopped, and the TBUT is recorded as 60 seconds (even if the actual time is longer).

[0142] Tear osmolality (TOsm). Before applying eye drops, blink mechanically 5-10 times (gently) to better distribute the tear film across the ocular surface. After gently retracting the lower eyelid, collect a tear sample using a TearLab osmometer (TearLab Corporation, San Diego, California) at the junction of the palpebral and bulbar conjunctiva, along the lower fornix, close to the base of the truncated nictitating membrane. Measure the osmolality using a TearLab osmometer according to the manufacturer's instructions.

[0143] Corneal fluorescein staining (CFS) assessment. Fluorescein staining was performed by instilling 20 μL of 2% fluorescein solution onto the ocular surface. After removing excess fluorescein, the cornea and superior conjunctiva were photographed under blue light using a digital camera. The degree of fluorescein staining on the cornea and superior conjunctiva was scored using a modified NEI scoring method. The cornea was divided into five sections, with the superior conjunctiva considered as one section. Each section was scored from 0 (none) to 3 (severe) based on the number, size, and punctate epithelial erosions.

[0144] Corneal sensitivity was measured in a quiet examination room using a Cochet-Bonnet tactile meter (Luneau, France) without anesthesia. For the tactile measurements, each rabbit was placed in a restraint bag 16 hours after the last dose of PS and before any sedation. A nylon filament was applied to the central cornea, the most sensitive area. The corneal tactile threshold test began with a full filament length of 6 cm and was gradually withdrawn by 0.5 cm until a positive response (complete blink) was observed in 3–5 attempts. The filament length simulating a positive response was used as the corneal sensitivity score.

[0145] Each enantiomer was formulated into a 0.2% gel and applied topically to the ocular surface as eye drops. Rabbits were treated with a single eye drop of either PS or excipient applied to both eyes once daily for 5 days. Measurements were performed at baseline (1 day before injection of concanavalin A) and at 5 and 7 days after the start of treatment, except for corneal fluorescein staining, which was measured only on day 5.

[0146] result Table 5. Effects of PS isomers 1 and 2 on corneal sensitivity and DED parameters on day 5:

[0147] Table 6. Effects of PS isomers 1 and 2 on corneal sensitivity and DED parameters on day 7:

[0148] These data also show Figure 4 middle.

[0149] discuss It was observed that, relative to the ConA and mediator entries in Tables 5 and 6, isomer 1 (( S )-Shulinic acid phosphate) and isomer 2 (( R The increased TBUT of sulindac phosphate (SAP) indicates that each enantiomer has therapeutic efficacy in treating DED. Isomer 1 (( S The longer TBUT of sulindac phosphate (PS) indicates that this enantiomer is more effective in treating DED. Similarly, each enantiomer of PS improved CFS, with isomer 1 (( S The lowest score was observed for sullinic acid phosphate (SAP). As expected, no different effects on osmotic pressure were observed for each enantiomer of PS. Only isomer 1 (( S Effects of sulindac phosphate (SAP) on corneal sensitivity—see Tables 5 and 6. These results indicate that isomer 1 improves corneal sensitivity.

[0150] in conclusion Results related to corneal sensitivity, osmotic pressure, TBUT, and CFS support the model in which isomer 1 (( S 1-Sullina phosphate is more effective than isomer 2. This supports the view that isomer 1 is more effective than isomer 2. S Sulindac phosphate (SAP) may be more effective in treating DED.

[0151] The observation of differential effects between isomers 1 and 2 in corneal sensitivity and dry eye-related experiments (see Tables 5 and 6) was surprising, as isomers 1 and 2 did not show differential effects in the CIPN model (Example 3).

[0152] Example 5: Efficacy of oral administration of racemic PS and its enantiomers in treating neuropathic pain in a CIPN mouse model. In this embodiment, the oral administration of PS enantiomers for the treatment of neuropathic pain in a CIPN mouse model was evaluated.

[0153] method CIPN was induced in mice using paclitaxel, consistent with experiments previously published in this paper. Once a diagnosis of CIPN was confirmed by lowering the mechanical abnormal pain threshold, racemic sulindac phosphate and isomer 1 were administered orally by gavage. S )-Shulinic acid phosphate) and isomer 2 (( R Sulindac phosphate (PS), once daily for three days. The dose of racemic PS was 50 mg / kg, the dose of isomer 2 was 50 mg / kg, and the dose of isomer 1 was 25 mg / kg or 50 mg / kg, as indicated. To determine mechanical abnormal pain, pain threshold response was measured three days after treatment using the widely established von Frey filament method, consistent with the method performed in the previous examples.

[0154] result Table 7. Effects of orally administered racemic PS, isomers 1 and 2 on CIPN:

[0155] discuss Compared to the mediator control, isomer 1 ((S)-sulindac phosphate) showed a significant increase in PWT at both doses, while isomer 2 ((R)-sulindac phosphate) also showed a significant increase in PWT at the test dose. Interestingly, at equivalent doses (even at lower doses), isomer 1 showed a significant difference in PWT recovery compared to isomer 2. This result suggests that both isomers can treat CIPN-related pain after oral administration, similar to the racemic PS, but isomer 1 ((S)-sulindac phosphate) appears to be more effective in this regard.

[0156] in conclusion The results of this embodiment support previous observations that topical application of either isoform of PS can treat neuropathic pain associated with CIPN. However, given the similar effects of topical application of isoform 1 ((S)-sulinacid phosphate) and isoform 2 ((R)-sulinacid phosphate) in a CIPN mouse model, the observation that oral application of isoform 1 ((S)-sulinacid phosphate) is more effective than oral application of isoform 2 ((R)-sulinacid phosphate) is unexpected. This supports the observation that isoform 1 ((S)-sulinacid phosphate is more effective than oral application of isoform 2 ((R)-sulinacid phosphate) when applied orally. S Sulindac phosphate (SPF) may be more effective in treating CIPN.

[0157] Example 6: Effects of oral administration of racemic PS and its enantiomers in a mouse model of migraine. method The nitroglycerin (NTG)-induced migraine mouse model (Bates et al., 2010) is a particularly useful and clinically relevant animal model for migraine. NTG induces activation and sensitization of primary afferent neurons and second-order trigeminal angiogenic neurons. These pathophysiologies are considered potential mechanisms contributing to migraine headache (as well as the recurrent activation of dural afferent neurons thought to occur in patients with recurrent migraine headache) and many craniofacial nociceptive symptoms. NTG also mediates hypersensitivity responses of facial skin and hind paws to non-noxious peripheral stimuli, indicating atypical pain, a manifestation of central sensitization. Therefore, the ability of NTG to trigger central sensitization makes this model more broadly applicable to migraine and other pain disorders associated with central sensitization.

[0158] In this embodiment, the PS enantiomer was evaluated in a mouse model of migraine.

[0159] animal: Adult male C57BL / 6J mice were purchased from the Jackson Laboratory (Bar Harbor, ME), and were 8 weeks old and weighed 20-30 g at the start of the experiment. Mice were housed in groups of four in an AAALAC-certified facility with free access to food and water. The experiment was conducted during the light cycle (7:00 AM to 7:00 PM), and the animals were euthanized by CO2 asphyxiation. Mice in each cage were randomly assigned to treatment groups. All studies were conducted by researchers unaware of the identities of the treatment groups.

[0160] The study was approved by the Stony Brook University Institutional Animal Care and Use Committee and followed the National Institutes of Health's guidelines for laboratory animal care and use. The animal research report complied with the ARRIVE guidelines (Kilkenny et al., 2010).

[0161] Migraine induction: We used an NTG-induced migraine mouse model similar to that described by Bates et al. (2010). Specifically, instead of intraperitoneal injection of NTG, 0.4 mg of finely crushed NTG tablets (Greenstone Brand) were administered sublingually. As a control, a 0.4 mg sublingual Practi-nitroglycerin analog tablet was used. The mechanoreceptive threshold decreased as early as 30 minutes after NTG administration and persisted for approximately 24 hours.

[0162] Treatment options for diagnosed neuropathic pain associated with migraines: Once a diagnosis of migraine is confirmed by lowering the mechanical abnormal pain threshold, racemic sulindac phosphate and isomer 1 should be administered orally within 30 minutes of the migraine diagnosis. S )-Shulinic acid phosphate) and isomer 2 (( R(Sullina phosphate). The dose of PS is 50 mg / kg, the dose of isomer 2 is 50 mg / kg, and the dose of isomer 1 is 25 mg / kg or 50 mg / kg, as indicated.

[0163] Mechanical abnormal pain assessment (von Frey test): To determine mechanical anomalous pain, the widely established von Frey filament method was used to measure the pain threshold response, consistent with the methods performed in the previous examples. A PWT test was performed 30 minutes after treatment to assess mechanical anomalous pain. The mechanical threshold, expressed in g, represents the force required to elicit a response from the animal to the von Frey filament.

[0164] Statistical analysis: Results are expressed as mean ± SEM. A difference was considered significant when P < 0.05.

[0165] result First, we confirmed the NTG model of migraine and then evaluated the role of PS enantiomers in treating migraine pain. In the first study, we used mice in six independent groups, three at the 30-minute time point and three at the 60-minute time point, as determining mechanical aberrant pain in the same animals within 30 minutes could influence the results. As shown in the table below, administration of NTG induced aberrant pain within 30 minutes of administration, consistent with the understanding that this compound rapidly triggers neuronal activity corresponding to central sensitization. For completeness, oral NTG placebo control had no effect on PWT (i.e., no aberrant pain was induced) compared to baseline (see Table 8A).

[0166] Table 8A. Validation of the NTG model:

[0167] Table 8B. Effects of orally administered racemic PS, isomers 1 and 2 on migraine pain:

[0168] discuss Administration of NTG produced atypical pain within 30 minutes, consistent with the understanding that this compound rapidly triggers central sensitization. For completeness, oral NTG placebo control had no effect on PWT (i.e., no atypical pain was produced) compared to baseline (see Table 8A).

[0169] As shown in Table 8B, compared with the mediator control, isomer 1 ((S)-sulindac phosphate) showed a significant increase in PWT at both doses. In contrast, isomer 2 ((R)-sulindac phosphate) did not show a significant difference compared with the mediator control. In fact, at both doses tested, isomer 1 ((S)-sulindac phosphate) showed a significant improvement compared with isomer 2 ((R)-sulindac phosphate). This result indicates that isomer 1 ((S)-sulindac phosphate) has a unique ability to treat migraine pain when administered orally.

[0170] in conclusion The results support the effectiveness of isomer 1 ((S)-sulindac phosphate) in this model, while isomer 2 is ineffective. This suggests that isomer 1 ((S)-sulindac phosphate) is effective in treating migraine pain when administered orally.

[0171] Example 7: Efficacy of oral administration of racemic PS and its enantiomers in treating neuropathic pain in a PTPN mouse model Given the significant efficacy of oral isomer 1 ((S)-sulindac phosphate) in treating neuropathic pain associated with CIPN and migraine, the efficacy of oral PS enantiomer in treating neuropathic pain was evaluated in a PTPN mouse model.

[0172] method animal: Adult male C57BL / 6J mice were purchased from the Jackson Laboratory (Bar Harbor, ME), and were 8 weeks old and weighed 20-30 g at the start of the experiment. Mice were housed in groups of four in an AAALAC-certified facility with free access to food and water. The experiment was conducted during the light cycle (7:00 AM to 7:00 PM), and the animals were euthanized by CO2 asphyxiation. Mice in each cage were randomly assigned to treatment groups. All studies were conducted by researchers unaware of the identities of the treatment groups.

[0173] The study was approved by the Stony Brook University Institutional Animal Care and Use Committee and followed the National Institutes of Health's guidelines for laboratory animal care and use. The animal research report complied with the ARRIVE guidelines (Kilkenny et al., 2010).

[0174] PTPN induction:Chronic compression injury was used to induce neuropathic pain associated with PTPN. Neuropathic pain was induced in 8-week-old male C57BL / 6J mice (approximately 25 g) under anesthesia. The left sciatic nerve was exposed by incising the skin and the connective tissue between the superficial gluteal muscle and the biceps femoris muscle. Two chromic catgut sutures were loosely tied around the sciatic nerve with 7-0 sutures, spaced 1 mm apart, to just block but not impede epineurial blood flow. For control sham-operated mice, a similar skin incision was made on the left side, but the sciatic nerve was not ligated. In both cases, the surgical wound was closed with muscle layer sutures and skin layer staples. Pain hypersensitivity testing was performed 5–7 days after surgery.

[0175] Treatment options for diagnosed PTPN-related neuropathic pain: Once a diagnosis of PTPN is confirmed by lowering the threshold for mechanical abnormal pain, oral administration of racemic sulindac phosphate and isomer 1 (( S )-Shulinic acid phosphate) and isomer 2 (( R Sulindac phosphate (PS), once daily for 10 days. The dose of PS is 50 mg / kg, the dose of isomer 2 is 50 mg / kg, and the dose of isomer 1 is 25 mg / kg.

[0176] Mechanical abnormal pain assessment (von Frey test): To determine mechanical anomalous pain, the widely established von Frey filament method was used to measure the pain threshold response, consistent with the methods performed in the previous examples. A PWT test was performed 30 minutes after treatment to assess mechanical anomalous pain. The mechanical threshold, expressed in g, represents the force required to elicit a response from the animal to the von Frey filament.

[0177] Statistical analysis: Results are expressed as mean ± SEM. A difference was considered significant when P < 0.05.

[0178] result Table 9. Effects of orally administered racemic PS and its isomers 1 and 2 on PTPN-related pain:

[0179] discuss Both isomer 1 ((S)-sulindac phosphate) and isomer 2 ((R)-sulindac phosphate) showed a significant increase in PWT at the tested doses. Interestingly, at lower doses, isomer 1 showed a similar and significant PWT recovery compared to isomer 2. This result suggests that both isomers can treat PTPN-related pain after oral administration, similar to the racemic PS, but isomer 1 ((S)-sulindac phosphate) appears to be more effective in this regard.

[0180] in conclusion The results support the efficacy of both isomer 1 ((S)-sulindac phosphate) and isomer 2 in this further central site-of-action challenging pain model when administered orally. However, based on the oral administration data for CIPN and migraine pain provided in this paper, isomer 1 ((S)-sulindac phosphate) is more effective in treating PTPN when administered orally, further suggesting the broad applicability of this compound in treating challenging pain indications. While not wishing to be bound by theory, the improved efficacy may be due to the enhanced ability of S-sulindac phosphate to reach key sites of action at therapeutically relevant concentrations.

[0181] Example 8: Comments on the therapeutic efficacy of PS enantiomers.

[0182] The results of this study demonstrate the efficacy of PS enantiomers in treating DED and corneal sensitivity. In particular, (S)-sulindac phosphate is especially effective in treating these indications.

[0183] Furthermore, the results of this study indicate that PS enantiomers are active in treating neuropathic pain and pain associated with central sensitization. This activity is mechanistically distinct from its ability to treat DED and improve corneal sensitivity. Indeed, treating the latter requires increasing neuronal activity, while treating pain, particularly neuropathic pain, requires reducing neuronal pain signal transduction, especially the ability to transduce pain signals generated at central sites of action. Without being bound by theory, these observations suggest that PS enantiomers have a dual function in influencing neuronal activity (similar to previously observed PS racemates), depending, for example, on the pathology or site of action involved in a specific indication.

[0184] The results presented here regarding the efficacy of PS enantiomers in treating neuropathic pain disorders are unprecedented. Demonstrating the efficacy of a compound for treating challenging pain indications, including neuropathic pain, typically requires validation in specific animal models of neuropathic pain, as described herein. However, given the extensive data generated by the inventors demonstrating the efficacy of PS in a variety of different animal models of neuropathic pain, and the observed accumulation of orally administered PS in brain regions associated with pain signaling, the data presented here regarding the efficacy of PS enantiomers in challenging pain indications suggest that the applicability of PS enantiomers in treating neuropathic pain indications is as broad as that of the PS racemic mixture. In fact, the results presented here regarding neuropathic pain are supported by earlier observations of the PS racemic mixture in treating CIPN-related neuropathic pain (see WO2022 / 251805, which is incorporated herein by reference in its entirety). Furthermore, the racemic form of PS has been shown to be effective for pain associated with diabetic peripheral neuropathy (DPN) (see WO2022 / 251806, which is incorporated herein by reference in its entirety). Additionally, the racemic form of PS has been shown to be effective in treating neuropathic pain associated with post-traumatic peripheral neuropathy (PTPN), postherpetic neuropathy (PHN), and corneal neuropathic pain by acting directly on neuronal signaling (see data and observations in WO2024 / 112725 and WO2024 / 112727, the contents of which are hereby incorporated by reference in their entirety). Therefore, this unprecedented combination of observations allows for the inference of the therapeutic suitability of PS enantiomers, particularly sulindac S-phosphate, for the treatment of neuropathic pain based on the observations presented herein.

[0185] In addition to the shared ability of the racemic and enantiomers of PS to treat the diseases described in this article, S The enhanced therapeutic activity of sulindac phosphate (PS) was particularly noteworthy and unexpected. In fact, considering the equivalence of PS enantiomers in other situations, such as local application in the CIPN model, ( S The increased activity of sulindac phosphate in treating DED and restoring corneal sensitivity is surprising.

[0186] Oral administration ( S When sulindac phosphate (SPF) is added, the improvement in its therapeutic activity, particularly in pain indications, is even more remarkable. In fact, compared with (… R Compared to sulindac phosphate, when administered orally, ( S Sulindac phosphate (SPF) has shown improved efficacy in treating neuropathic pain associated with CIPN and PTPN. Furthermore, it is comparable to (…R Compared to sulindac phosphate, when administered orally, ( S Sulindac phosphate (SFP) has shown improving effects in treating migraine pain. The migraine model used in this study utilizes NTG, which is known to induce central sensitization. Therefore, ( S Efficacy of sulindac phosphate in this migraine pain model ( S Sulindac phosphate has potential therapeutic activity in treating pain associated with central sensitization.

[0187] The therapeutic efficacy of orally administered racemic PS for the challenging pain indication studied in this paper is itself unexpected. In fact, previous observations of racemic PS for specific forms of neuropathic pain involved local administration and failed to demonstrate the efficacy of orally administered racemic PS for such indications. With local administration, PS is applied to areas of high concentration of peripheral sensory neurons, allowing for absorption and transport to the central site of action in sufficiently high quantities to achieve analgesia. With oral administration, PS is exposed to the intestinal endothelial surface, which differs from the skin epithelial surface exposed with local administration in terms of environment, structure, neuronal physiology, and concentration. Oral administration is generally unsuitable due to the instability of PS in the blood, the potential degradation of the active compound in the intestinal environment or blood after absorption, and the required PS concentrations to overcome these issues are considered inappropriate. Therefore, it was unexpected that orally administered PS could achieve analgesia for indications where pain originates in the central nervous system.

[0188] In addition to the unexpected activity of the racemic PS upon oral administration, our observations suggest that oral administration of the racemic PS showed significant activity in neuropathic pain models associated with CIPN, PTPN, and migraine pain (related to central sensitization). S When )-sulindac phosphate, ( S )-Sullina phosphate ratio ( R Sulindac phosphate (SPH) is more effective. This is particularly surprising given the functional similarity of enantiomers when administered locally in the CIPN model. While not wishing to be bound by theory, the evidence in this paper suggests that, when administered orally, ( S Sulindac phosphate (PS) may accumulate more readily at key central sites of action in pain generation. Indeed, orally administered PS has been shown to accumulate in areas of the brain associated with pain signaling and / or sensation, even when administered orally (via the passage of the vagus nerve from the stomach) (as provided by data and observations in WO2024 / 112725 and WO2024 / 112727). Therefore, compared with ( R Compared to sulindac phosphate, ( SSulindac phosphate, when administered orally, may reach key pain-generating sites in the brain at more therapeutically effective concentrations, thus ( S Sulindac phosphate (SPF) may be more widely applicable to a variety of challenging pain indications when administered orally, as observed in this paper. Regardless of the mechanism, after oral administration ( S The improvement in the ability of sulindac phosphate was unexpected.

[0189] It should be understood that the above description of the inventor's work is merely illustrative and may be modified, while such modifications remain within the scope and spirit of the present invention.

Claims

1. A compound having the following structure: (( S )-Sullina phosphate).

2. A composition comprising ( S )-Sullina phosphate.

3. The composition of claim 2, wherein ( S The enantiomeric excess of sulindac phosphate is at least: 50%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%; or 100%.

4. The composition according to claim 2 or 3, wherein ( S The enantiomer of sulindac phosphate is in excess of at least: 80%, 90%, 96% or 98%.

5. The composition according to any one of claims 2 to 4, wherein ( S The enantiomer of sulindac phosphate is in excess of at least 96%.

6. The composition according to any one of claims 2 to 5, wherein ( S The enantiomer of sulindac phosphate is in excess of at least 98%.

7. The composition according to any one of claims 2 to 6, wherein the composition is a pharmaceutical composition.

8. The pharmaceutical composition of claim 7, further comprising at least one excipient.

9. The pharmaceutical composition of claim 7 or 8, wherein the composition is formulated for topical application.

10. The pharmaceutical composition of any one of claims 7 to 9, wherein the composition is formulated as a solution, cream, gel (e.g., hydrogel), lotion, ointment, foam, and / or spray.

11. The pharmaceutical composition according to any one of claims 7 to 10, wherein ( S The concentration of sulindac phosphate is from about 0.05% w / w to about 15% w / w of the pharmaceutical composition.

12. A method for preparing enantiomer-enriched ( ) by chromatography S A method for sulindac phosphate, the method comprising: a. Separation of mixtures containing sulinac phosphate enantiomers using a chiral stationary phase; as well as b. Separation of enantiomers enriched ( S )-Sullina phosphate.

13. The method of claim 12, wherein the separated ( S An excess of the enantiomer of sulinic acid phosphate relative to the mixture was increased.

14. The method of claim 12 or 13, wherein the separated ( S The enantiomeric excess of sulindac phosphate is at least: 50%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%; or 100%.

15. The method of any one of claims 12 to 14, wherein the separated ( S The enantiomer of sulindac phosphate is in excess of at least 96%.

16. The method of any one of claims 12 to 15, wherein the separated ( S The enantiomer of sulindac phosphate is in excess of at least 98%.

17. The method of any one of claims 12 to 16, wherein the chromatography is supercritical fluid chromatography.

18. The method of any one of claims 12 to 17, wherein step b) further comprises detecting the enantiomer with a UV detector.

19. The method of any one of claims 12 to 18, wherein the chiral stationary phase is an amylose derivative coated on silica gel, for example, wherein the amylose derivative is amylose-tris(3,5-dimethylphenylcarbamate).

20. The method of any one of claims 12 to 19, wherein the method uses a mobile phase comprising methanol and CO2.

21. The method of any one of claims 12 to 20, wherein the enantiomer excess is determined by chromatography, such as supercritical fluid chromatography.

22. A kind of ( S )-Sullina phosphate, which can be obtained by the method described in any one of claims 12 to 21.

23. A kind of ( S Sulinic acid phosphate (SAP) is used for treatment.

24. A kind of ( S Sulinic acid phosphate (SAP) is used to treat dry eye syndrome.

25. A kind of ( S Sulindac phosphate (SPH) is used to treat neuropathic pain associated with chemotherapy-induced peripheral neuropathy (CIPN).

26. A kind of ( S Sulindac phosphate (SPH) is used to treat neuropathic pain associated with post-traumatic peripheral neuropathy (PTPN).

27. A kind of ( S Sulinic acid phosphate (SAP) is used to treat migraine pain.

28. A method for treating dry eye in a patient in need, the method comprising administering to the patient a therapeutically effective amount of ( S )-Sullina phosphate.

29. A method for treating neuropathic pain associated with chemotherapy-induced peripheral neuropathy in a patient in need, the method comprising administering to the patient a therapeutically effective dose of ( S )-Sullina phosphate.

30. A method for treating neuropathic pain associated with post-traumatic peripheral neuropathy in a patient in need, the method comprising administering to the patient a therapeutically effective dose of ( S )-Sullina phosphate.

31. A method for treating migraine pain in a patient in need, the method comprising administering to the patient a therapeutically effective dose of ( S )-Sullina phosphate.

32. A kind of ( S Sulinic acid phosphate is used to manufacture drugs for the treatment of dry eye.

33. A kind of ( S Sulinic acid phosphate is used to manufacture drugs for the treatment of neuropathic pain associated with chemotherapy-induced peripheral neuropathy (CIPN).

34. A kind of ( S Sulinic acid phosphate is used to manufacture drugs for the treatment of neuropathic pain associated with post-traumatic peripheral neuropathy.

35. A kind of ( S Sulinic acid phosphate is used to manufacture drugs for treating migraine pain.

36. The method according to claims 23 to 27 ( S )-Sullina phosphate, the method as described in claims 28 to 31, or the use as described in claims 32 to 35, wherein ( S Sulindac phosphate is a topical medication.

37. The method of claim 23, 24 or 36 ( S )-Sullina phosphate, the method as described in claim 28 or 36, or the use as described in claim 32 or 36, wherein ( S Sulindac phosphate is applied to the eye or tissues around the eye, such as the eyelid.

38. The method according to claims 23 to 27 ( S )-Sullina phosphate, the method as described in claims 28 to 31, or the use as described in claims 32 to 35, wherein ( S Sulindac phosphate is administered orally.

39. As described in claim 38 ( S )-Sullina phosphate, method or use, wherein the ( S Sulinic acid phosphate is formulated into liquid or solid dosage forms.

40. As described in claim 39 ( S Sulinic acid phosphate, methods, or uses, wherein the liquid dosage form is a pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup, or elixir.

41. As described in claim 39 ( S Sulinic acid phosphate, methods or uses, wherein the solid dosage form is a capsule, tablet, pill, powder or granule.

42. The method of claim 38 to 41 ( S )-Sullina phosphate, method or use, wherein the ( S Sulindac phosphate is administered orally at dose levels of about 0.01 mg / kg to about 100 mg / kg, about 0.05 mg / kg to about 50 mg / kg, or about 0.1 mg / kg to about 10 mg / kg of the subject's body weight, such as about 1 mg / kg to about 5 mg / kg, such as about 3 mg / kg of the subject's body weight.

43. The method of claim 38 to 42 ( S )-Sullina phosphate, method or use, wherein the ( S Sulindac phosphate is administered orally in doses of about 1 mg to about 2000 mg, about 100 mg to about 1500 mg, about 200 mg to about 100 mg, about 50 mg to about 400 mg, for example about 100 mg to about 350 mg, for example about 150 mg to about 300 mg, for example about 150 mg to about 250 mg.

44. The method of claim 38 to 43 ( S )-Sullina phosphate, method or use, wherein the ( S Sulindac phosphate is administered orally at a dose of about 250 mg to about 300 mg, preferably about 250 mg.

45. The method of claim 38 to 44 ( S )-Sullina phosphate, method or use, wherein the ( S Sulindac phosphate is administered orally once daily.

46. ​​The method of claim 38 to 45 ( S )-Sullina phosphate, method or use, wherein the ( S Sulindac phosphate should be administered orally at least twice, three times, or four times daily.

47. The method of claim 38 to 45 ( S )-Sullina phosphate, method or use, wherein the ( S Sulindac phosphate is administered orally two or three times daily.

48. The method of claim 38 to 47 ( S )-Sullina phosphate, method or use, wherein the ( S Sulindac phosphate is administered orally at a dose of approximately 150 mg to approximately 200 mg twice daily.

49. The method of claim 38 to 48 ( S )-Sullina phosphate, method or use, wherein the ( S Sulindac phosphate is administered orally at a daily dose of about 300 mg to about 400 mg.

50. The method of claim 38 to 47 ( S )-Sullina phosphate, method or use, wherein the ( S Sulindac phosphate is administered orally at a daily dose of about 250 mg to about 300 mg (e.g., about 250 mg) two or three times a day.

51. The method as described in any one of claims 38 to 47 or 50. S )-Sullina phosphate, method or use, wherein the ( S Sulindac phosphate is administered orally at a daily dose of approximately 500 mg to up to approximately 900 mg.

52. The method of claim 38 to 51 ( S )-Sullina phosphate, method or use, wherein the ( S Sulindac phosphate is administered orally in the form of a pharmaceutical composition.

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