Magnesium-containing oxytocin formulations and methods of use

Abstract

To provide an oxytocin peptide formulation capable of faster on-set of the analgesic effect.SOLUTION: Provided are methods and compositions comprising an oxytocin peptide and a magnesium salt for treating pain via craniofacial mucosal administration (e.g., intranasal administration). The methods and magnesium containing oxytocin peptide formulations described herein provide faster, stronger and longer lasting analgesic effect compared to oxytocin alone.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 62 / 100,862, filed January 7, 2015, the disclosure of which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION The present invention relates to compositions comprising an oxytocin peptide and a magnesium salt. Also disclosed is a method for treating pain (e.g., migraine) comprising co-administering an oxytocin peptide and a magnesium salt. [Background technology]

[0003] BACKGROUND OF THE INVENTION Oxytocin is a naturally occurring nine-amino acid neuropeptide produced primarily in the paraventricular and supraoptic nuclei of the mammalian hypothalamus. It is released into the central nervous system via distributed neural pathways and into the peripheral circulation via the posterior pituitary gland. Intramuscular or intravenous infusion of synthetic oxytocin (Pitocin®) is currently approved in the United States to produce or improve uterine contractions to promote vaginal delivery and to manage postpartum hemorrhage. Intranasal oxytocin (Syntocinon®) was approved in the United States from 1960 to 1997 to stimulate milk ejection and promote breastfeeding. Syntocinon® nasal spray was withdrawn from the U.S. market at the request of the manufacturer, but intranasal oxytocin is still sold in countries outside the United States, such as Switzerland, Portugal, and Brazil. Recently, the use of oxytocin peptides in the treatment of pain, including headache, via intranasal administration has been demonstrated. See WO2007 / 025249A2 and WO2007 / 025286A2, the disclosures of which are incorporated herein by reference.

[0004] Pain is a sensation mediated in part by the activation of certain brain structures. Pain is typically elicited when specialized neurons called nociceptors, which innervate the skin or other peripheral tissues, are activated by mechanical, thermal, chemical, or other noxious stimuli. Pain can also occur when peripheral or central nervous structures involved in pain processing become hyperactive, for example, as a result of trauma, ischemia, or inflammation. Other causes of pain include disease-specific processes, metabolic disorders, muscle spasms, and the occurrence of neuropathic events or syndromes. Despite the availability of a wide range of pharmacotherapy, including non-opioids (e.g., acetaminophen and nonsteroidal anti-inflammatory drugs or NSAIDs), opioids, and adjuvant analgesics (e.g., gabapentin), pain continues to afflict millions in the United States alone and remains a significant burden on patients, healthcare, and businesses. Oxytocin has been shown to reduce trigeminal nerve-related pain, especially chronic pain, such as trigeminal neuralgia and migraine.Human clinical trials have demonstrated the effectiveness of intranasal oxytocin in treating migraine.However, these trials have shown that the latency time for analgesia caused by intranasal oxytocin is approximately 2 hours, and the maximum analgesic effect does not occur until about 4 hours after administration.Therefore, there is a need for an oxytocin peptide formulation that can exert an analgesic effect more quickly. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2007 / 025249 [Patent Document 2] International Publication No. 2007 / 025286 Summary of the Invention [Means for solving the problem]

[0006] (Brief Summary of the Invention) Methods and compositions comprising oxytocin peptides and magnesium salts are provided for treating pain via craniofacial mucosal administration (e.g., intranasal administration). The methods and magnesium-containing oxytocin peptide formulations described herein provide faster, stronger, and longer-lasting analgesic effects compared to oxytocin alone.

[0007] In one aspect, the present invention provides a method for treating pain, comprising administering an effective dose of an oxytocin peptide and a magnesium salt to a subject in need thereof, wherein co-administration of the oxytocin peptide and the magnesium salt results in synergistic analgesia. The oxytocin peptide and the magnesium salt may be co-administered together or sequentially. In some embodiments, the oxytocin peptide is administered together with the magnesium salt in the same unit dose or in separate unit doses or formulations. In some embodiments, the oxytocin peptide and the magnesium salt are administered sequentially. For example, the oxytocin peptide is administered a period of time after administration of the magnesium salt. In some embodiments, the subject is a human.

[0008] Oxytocin peptide and magnesium salt can be administered to a subject in need thereof via the same route or via different routes.In some embodiments, oxytocin peptide is administered via craniofacial mucosal administration (for example, nasal, buccal, sublingual or ocular administration).In one embodiment, both oxytocin peptide and magnesium salt are administered intranasally in the same formulation.

[0009] In some embodiments, the oxytocin peptide is human oxytocin consisting of Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly (SEQ ID NO: 1). In some embodiments, an effective dose of the oxytocin peptide is about 0.5 μg to about 2000 μg, preferably about 8 μg to about 1000 μg, and more preferably about 15 μg to about 120 μg. In some embodiments, an effective dose of the magnesium salt administered provides about 50 μg to about 68 mg of magnesium, preferably about 50 μg to about 34 mg of magnesium, and more preferably about 1 mg to about 3 mg of magnesium. In some embodiments, the magnesium salt comprises magnesium citrate and / or magnesium chloride administered in an amount providing about 50 μg to about 68 mg of magnesium, or about 50 μg to about 34 mg of magnesium, or about 1 mg to about 3 mg of magnesium. In some embodiments, the magnesium salt is magnesium citrate or magnesium chloride administered in an amount providing about 50 μg to about 68 mg of magnesium, or about 50 μg to about 34 mg of magnesium, or about 1 mg to about 3 mg of magnesium. In some embodiments, an effective dose of magnesium salt is about 0.48 mg to about 600 mg of magnesium citrate, preferably about 0.48 mg to about 300 mg of magnesium citrate, more preferably about 10 mg to about 30 mg of magnesium citrate. In some embodiments, an effective dose of oxytocin peptide and magnesium salt comprises about 0.5 μg to about 2000 μg or about 15 μg to about 120 μg (e.g., about 66 μg) of oxytocin peptide administered in an aqueous solution containing about 1% to about 25% (preferably, about 10% to about 14%, e.g., about 12%) (w / v) magnesium citrate. In some embodiments, an effective dose of oxytocin peptide and magnesium salt comprises about 0.5 μg to about 2000 μg or about 15 μg to about 120 μg (e.g., about 60 μg or about 66 μg) of oxytocin peptide administered in an aqueous solution containing about 0.11% to about 2.8% (preferably, about 1.1% to about 1.6%, e.g., about 1.36%) (w / v) magnesium.

[0010] In some embodiments, pain treatable by the methods includes any pain treatable with oxytocin peptides (e.g., orofacial and craniofacial pain (e.g., headache), neck pain (e.g., occipital neuralgia), shoulder pain, or upper limb pain). In some embodiments, the pain is chronic pain, acute pain, or incident pain. In some embodiments, the pain is headache or facial pain. In some embodiments, the pain is trigeminal nerve-associated pain. In some embodiments, the pain is migraine. In some embodiments, the pain is cervical nerve-associated pain.

[0011] In one embodiment, the present invention provides a method for treating migraine headaches, comprising administering (e.g., intranasally) to a subject in need thereof effective doses of an oxytocin peptide and a magnesium salt, wherein co-administration of the oxytocin peptide and the magnesium salt results in synergistic analgesia.

[0012] In one aspect, the present invention provides magnesium-containing oxytocin peptide formulations and their use in the treatment of pain. Accordingly, compositions comprising an oxytocin peptide and a magnesium salt are provided, wherein the oxytocin peptide and magnesium salt are present in amounts that provide synergistic analgesia when used in the treatment of pain. In some embodiments, the oxytocin peptide is human oxytocin consisting of Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly (SEQ ID NO: 1). In some embodiments, the magnesium salt comprises magnesium citrate and / or magnesium chloride. In some embodiments, the magnesium salt comprises magnesium citrate and magnesium chloride. In some embodiments, the magnesium salt is magnesium citrate or magnesium chloride. In some embodiments, the composition is a liquid formulation comprising about 0.01 mg / mL to about 16 mg / mL of oxytocin peptide (preferably, about 0.1 mg / mL to about 2 mg / mL, more preferably, about 0.15 mg / mL to about 1.5 mg / mL or about 0.33 mg / mL). In some embodiments, the composition is a liquid formulation comprising a magnesium salt in an amount providing about 1 mg / mL to about 30 mg / mL of magnesium (or about 5 mg / mL to about 30 mg / mL, about 10 mg / mL to about 30 mg / mL, preferably about 11 mg / mL to about 15 mg / mL, or about 13 mg / mL, or about 12 mg / mL). In some embodiments, the composition further comprises one or more excipients, vehicles, emulsifiers, stabilizers, preservatives, mucoadhesives, antimicrobial agents, buffers, and / or other additives. In some embodiments, the composition has a pH of about 2 to about 7 (preferably about 4.5). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0013] In some embodiments, a pharmaceutical composition is provided comprising an oxytocin peptide and a magnesium salt and a pharmaceutically acceptable carrier, wherein the oxytocin peptide and the magnesium salt are present in amounts that provide synergistic analgesia when used in the treatment of pain.

[0014] In some embodiments, the composition is adapted for craniofacial mucosal administration (e.g., nasal, buccal, sublingual, or ocular administration). In some embodiments, the composition is adapted for intranasal administration, and the composition may further comprise a device for intranasal administration (e.g., a nasal pump apparatus, e.g., a nasal pump apparatus comprising a reservoir bottle attached to an aerosolizer). In some embodiments, the nasal pump apparatus comprises one or more of the following: (i) a filter to prevent backflow, (ii) a metal-free flow path, and (iii) a gamma-ray stable plastic material. In some embodiments, the nasal pump apparatus provides a metered dose (e.g., about 50 to about 150 μL per spray or about 50 μL per spray).

[0015] Also provided is a method for treating pain in a subject in need thereof, comprising administering intranasally to the subject in need thereof an effective dose of a magnesium-containing oxytocin peptide formulation described herein.

[0016] Further provided is the magnesium-containing oxytocin peptide formulation described herein for use in a method for treating pain in a subject in need thereof. Also provided is the use of the magnesium-containing oxytocin peptide formulation described herein in the manufacture of a medicament for treating pain.

[0017] Also provided are kits containing the magnesium-containing oxytocin peptide formulations described herein contained in a device for intranasal administration, such as a nasal pump device, and suitable packaging. The kits may further include instructions for administering the magnesium-containing oxytocin peptide formulation to a subject in need thereof. In an embodiment of the present invention, for example, the following items are provided: (Item 1) 1. A method for treating pain, comprising administering to a subject in need thereof effective doses of an oxytocin peptide and a magnesium salt, wherein co-administration of the oxytocin peptide and the magnesium salt results in synergistic analgesia. (Item 2) 10. The method of claim 1, wherein the oxytocin peptide is administered simultaneously with the magnesium salt. (Item 3) 10. The method of claim 1, wherein the oxytocin peptide is administered before or after administration of the magnesium salt. (Item 4) 4. The method of any one of items 1 to 3, wherein the oxytocin peptide is administered via craniofacial mucosal administration. (Item 5) 5. The method of claim 4, wherein the oxytocin peptide is administered via intranasal administration. (Item 6) 6. The method of claim 5, wherein the oxytocin peptide and the magnesium salt are administered via intranasal administration. (Item 7) 7. The method according to any one of items 1 to 6, wherein the magnesium salt comprises magnesium chloride. (Item 8) 8. The method according to any one of items 1 to 7, wherein the magnesium salt comprises magnesium citrate. (Item 9) Item 9. The method according to item 8, wherein the effective dose of the oxytocin peptide is about 0.5 μg to about 2000 μg. (Item 10) 9. The method of claim 8, wherein the effective dose of the magnesium salt provides about 50 μg to about 68 mg of magnesium. (Item 11) 9. The method of claim 8, wherein the effective dose of the oxytocin peptide and the magnesium salt comprises about 15 μg to about 120 μg of the oxytocin peptide administered in an aqueous solution containing about 1.1% to about 1.6% (w / v) magnesium. (Item 12) 9. The method of claim 8, wherein the effective dose of the oxytocin peptide and the magnesium salt comprises about 66 μg of the oxytocin peptide administered in an aqueous solution containing about 1.36% magnesium. (Item 13) 13. The method according to any one of items 1 to 12, wherein the pain is chronic pain. (Item 14) 13. The method according to any one of items 1 to 12, wherein the pain is acute pain. (Item 15) 13. The method according to any one of items 1 to 12, wherein the pain is incident pain. (Item 16) 13. The method according to any one of items 1 to 12, wherein the pain is headache or facial pain. (Item 17) 13. The method according to any one of items 1 to 12, wherein the pain is trigeminal nerve-associated pain. (Item 18) 13. The method according to any one of items 1 to 12, wherein the pain is a migraine headache. (Item 19) 13. The method according to any one of items 1 to 12, wherein the pain is neck pain, shoulder pain, or upper limb pain. (Item 20) 13. The method according to any one of items 1 to 12, wherein the pain is cervical nerve-associated pain. (Item 21) 21. The method according to any one of items 1 to 20, wherein the oxytocin peptide is human oxytocin (SEQ ID NO: 1). (Item 22) 1. A composition comprising an oxytocin peptide and a magnesium salt, wherein the oxytocin peptide and the magnesium salt are present in amounts that provide synergistic analgesia when used in the treatment of pain. (Item 23) 23. The composition of claim 22, wherein the oxytocin peptide is human oxytocin (SEQ ID NO: 1). (Item 24) 24. The composition according to item 22 or 23, wherein the magnesium salt comprises magnesium citrate and / or magnesium chloride. (Item 25) 25. The composition of claim 24, wherein the magnesium salts include magnesium chloride and magnesium citrate. (Item 26) 26. The composition according to any one of items 22 to 25, wherein the composition is a liquid formulation comprising about 0.01 mg / mL to about 16 mg / mL of the oxytocin peptide. (Item 27) 27. The composition of claim 26, wherein the liquid formulation comprises about 0.15 mg / mL to about 1.5 mg / mL of the oxytocin peptide. (Item 28) 28. The composition of any one of items 22 to 27, wherein the composition is a liquid formulation comprising the magnesium salt in an amount providing from about 3 mg / mL to about 30 mg / mL of magnesium. (Item 29) 29. The composition of claim 28, wherein the liquid formulation comprises about 11 mg / mL to about 15 mg / mL of magnesium. (Item 30) 30. The composition according to any one of items 22 to 29, further comprising one or more excipients, vehicles, emulsifiers, stabilizers, preservatives, mucoadhesives, antimicrobial agents, buffers and / or other additives. (Item 31) 30. The composition according to any one of items 22 to 29, wherein the composition has a pH of about 4.5. (Item 32) The composition according to any one of items 22 to 31, wherein the composition is suitable for nasal administration. (Item 33) 33. The composition according to item 32, further comprising a device for intranasal administration. (Item 34) 34. The composition according to item 33, wherein the device for intranasal administration is a nasal pump device. (Item 35) Item 35. The composition of item 34, wherein the nasal pump device comprises a reservoir bottle attached to a pump actuator. (Item 36) 36. The composition of claim 35, wherein the pump actuator is metered to deliver a specific volume of about 50 μL. (Item 37) 35. The composition of claim 34, wherein the nasal pump device comprises a reservoir bottle attached to an aerosolizer. (Item 38) the nasal pump device comprising: (i) a filter to prevent backflow; (ii) metal-free flow paths, and (iii) Gamma-ray stable plastic materials 38. The composition according to any one of items 34 to 37, comprising one or more of: (Item 39) 33. A method for treating pain, comprising administering to a subject in need thereof an effective dose of the composition of any one of items 22 to 32 and a pharmaceutically acceptable carrier. (Item 40) A kit comprising the composition according to any one of items 22 to 38 and packaging material. (Item 41) 41. The kit of claim 40, further comprising instructions for administering the composition according to the method of claim 39. [Brief explanation of the drawings]

[0018] [Figure 1]Effects of magnesium chloride or magnesium lactate in a rat model of facial thermal pain. Rats were treated with saline, 15% magnesium chloride, or 1% magnesium lactate, and withdrawal latencies were measured immediately before and 1, 2, and 3 hours after treatment.

[0019] [Figure 2] Dose-dependence of the analgesic effect of intranasally applied magnesium citrate in a rat model of facial thermal pain. Rats were treated with 3, 6, 10, or 12% magnesium citrate, and withdrawal latencies were measured immediately before treatment and at 15, 30, 45, 60, 120, 180, 240, and 300 minutes after treatment.

[0020] [Figure 3] Dose-dependence of the analgesic effect of intranasally administered oxytocin in a rat model of facial thermal nociception. Rats were treated with 1, 4, or 8 μg of oxytocin, and withdrawal latencies were measured immediately before treatment and 15, 30, 45, 60, 120, 180, 240, and 300 minutes after treatment.

[0021] [Figure 4A] Analgesic effect of intranasal application of 1 μg of oxytocin in 6% magnesium citrate solution. The difference in response latency was measured 15, 30, 45, 60, 120, 180, 240, and 300 minutes after treatment for the calculated additive effects of 1 μg of oxytocin alone, 6% magnesium citrate alone, 1 μg of oxytocin in 6% magnesium citrate solution, and the actual application of 1 μg of oxytocin in 6% magnesium citrate solution.

[0022] [Figure 4B] Figures 4B, 4C, and 4D. Analgesic effect of intranasal application of 1 μg of oxytocin in 3, 6, or 12% magnesium citrate solution. The difference in response latency 45 minutes after treatment was measured for oxytocin alone, magnesium citrate alone, the calculated additive effect of magnesium citrate solution containing oxytocin, and the actual application of magnesium citrate solution containing oxytocin. [Figure 4C] Figures 4B, 4C, and 4D. Analgesic effect of intranasal application of 1 μg of oxytocin in 3, 6, or 12% magnesium citrate solution. The difference in response latency 45 minutes after treatment was measured for oxytocin alone, magnesium citrate alone, the calculated additive effect of magnesium citrate solution containing oxytocin, and the actual application of magnesium citrate solution containing oxytocin. [Figure 4D] Figures 4B, 4C, and 4D. Analgesic effect of intranasal application of 1 μg of oxytocin in 3, 6, or 12% magnesium citrate solution. The difference in response latency 45 minutes after treatment was measured for oxytocin alone, magnesium citrate alone, the calculated additive effect of magnesium citrate solution containing oxytocin, and the actual application of magnesium citrate solution containing oxytocin.

[0023] [Figure 5] Analgesic effect of intranasal application of 4 μg oxytocin in 6% magnesium citrate solution. The difference in response latency 120 minutes after treatment was measured for the calculated additive effect of 4 μg oxytocin alone, 6% magnesium citrate alone, 4 μg oxytocin in 6% magnesium citrate solution, and the actual application of 4 μg oxytocin in 6% magnesium citrate solution.

[0024] [Figure 6A] Analgesic effect of intranasal application of 8 μg oxytocin in 12% magnesium citrate solution. Differences in response latencies were measured 15, 30, 45, 60, 120, 180, 240, and 300 minutes after treatment for the calculated additive effects of 8 μg oxytocin alone, 12% magnesium citrate alone, 8 μg oxytocin in 12% magnesium citrate solution, and actual application of 8 μg oxytocin in 12% magnesium citrate solution.

[0025] [Figure 6B]Figures 6B, 6C, and 6D. Analgesic effect of intranasal application of 8 μg of oxytocin in 3, 6, or 12% magnesium citrate solution. Differences in response latency 15 minutes after treatment were measured for oxytocin alone, magnesium citrate alone, the calculated additive effect of magnesium citrate solution containing oxytocin, and the actual application of magnesium citrate solution containing oxytocin. [Figure 6C] Figures 6B, 6C, and 6D. Analgesic effect of intranasal application of 8 μg of oxytocin in 3, 6, or 12% magnesium citrate solution. Differences in response latency 15 minutes after treatment were measured for oxytocin alone, magnesium citrate alone, the calculated additive effect of magnesium citrate solution containing oxytocin, and the actual application of magnesium citrate solution containing oxytocin. [Figure 6D] Figures 6B, 6C, and 6D. Analgesic effect of intranasal application of 8 μg of oxytocin in 3, 6, or 12% magnesium citrate solution. Differences in response latency 15 minutes after treatment were measured for oxytocin alone, magnesium citrate alone, the calculated additive effect of magnesium citrate solution containing oxytocin, and the actual application of magnesium citrate solution containing oxytocin.

[0026] [Figure 7] Analgesic effect of intranasal application of oxytocin (8 μg) in 20% magnesium sulfate heptahydrate solution 120 minutes after intranasal administration.

[0027] [Figure 8] Analgesic effects observed 30, 60, 90, 120, 180 minutes and 24 hours after intranasal administration of nasal oxytocin at doses of 0 (vehicle), 193, 385 and 768 μg in a rat paw inflammation model. DETAILED DESCRIPTION OF THE INVENTION

[0028] (Detailed Description of the Invention) The present invention provides, inter alia, compositions comprising oxytocin peptides and magnesium salts and methods for treating pain by craniofacial administration (eg, intranasal administration) of the magnesium-containing oxytocin peptide formulations.

[0029] (definition) As used herein, unless otherwise specified, the term "treatment" or "treating pain" refers to administering an agent of interest to a subject, where the agent relieves pain or prevents the painful condition for which the subject is being treated.

[0030] Although analgesia in the strictest sense is the absence of pain, as used herein, "analgesia" or "analgesic effect" refers to a reduction in pain perceived by a subject, including a reduction in hyperalgesia and / or allodynia. "Analgesia" or "analgesic effect" also includes a reduction in the frequency of pain.

[0031] "Analgesic agent," "analgesic agent," or "analgesic drug" refers to any biomolecule, drug, or active agent that relieves or prevents pain episodes or reduces the frequency of pain episodes.

[0032] "Synergy," "synergy," or "synergistic effect" refers to the combined action of two or more compounds in such a way that one complements or potentiates the action of the other, thereby resulting in an effect that is greater than what would be predicted or expected by adding together the effects of a given dose of the two or more compounds when administered individually. A "synergistic analgesic effect" is said to be achieved when the combined use of two or more analgesic agents results in an overall reduction in pain intensity or sensitivity to painful stimuli (allodynia and / or hyperalgesia) that is greater than the analgesic or analgesic effect of either of them individually in equal amounts that would be predicted or expected by adding together the effects of the individual agents. "Synergistic analgesia" or "synergistic analgesic effect" is also considered to be achieved when the use of two or more analgesic agents in combination results in a more rapid onset of analgesia or analgesia and / or a longer lasting analgesic effect than would occur following the administration of an equal amount of each analgesic agent alone.

[0033] "Acute pain" refers to pain that develops suddenly due to a specific cause (such as injury, infection, or inflammation) and lasts for a limited period of time (as opposed to chronic pain). "Chronic pain" refers to a persistent state of pain. Chronic pain is often associated with a long-lasting or intractable medical condition or disease. Chronic pain can also refer to a pain state that occurs frequently. For example, if a person experiences headaches 15 days or more per month, the person is considered to have "chronic migraine." "Episodic pain" refers to pain that occurs recurringly but occasionally. For example, in people who experience episodic migraine, weeks and months may pass between migraine attacks.

[0034] "Craniofacial mucosal administration" refers to delivery to the mucosal surfaces of the nose, nasal passages, and nasal cavity; the mucosal surfaces of the oral cavity including the gingiva (gums), floor of the mouth, lips, tongue, sublingual oral surfaces (including the lingual frenulum and floor of the mouth), and mucosal surfaces of or around the eye (including the conjunctiva, lacrimal gland, nasolacrimal duct) and the upper or lower eyelids and mucous membranes of the eye.

[0035] "Intranasal administration" or "administered intranasally" refers to delivery to the nose, nasal passages, or nasal cavity by spray, drops, powder, gel, film, inhalant, or other means.

[0036] The "inferior region of the nasal cavity" generally refers to the region of the nasal cavity where the middle and inferior turbinates protrude and that is significantly innervated by the trigeminal nerve. The "superior region of the nasal cavity" is defined by the upper third and cribriform plate region, where olfactory innervation is located.

[0037] "Subject" or "patient," as used herein, refers to a mammal, including, but not limited to, a human. Mammals include, but are not limited to, farm animals (e.g., cows), sport animals, pets (e.g., guinea pigs, cats, dogs, rabbits, and horses), primates, mice, and rats. In one embodiment, the subject is a human.

[0038] As used herein, "oxytocin peptide" refers to a substance having biological activity related to natural oxytocin. The oxytocin peptide may be a naturally occurring endogenous peptide, a fragment thereof, an analog, or a derivative thereof. The oxytocin peptide may also be a non-endogenous peptide, a fragment thereof, an analog, or a derivative thereof. In one embodiment, the oxytocin peptide is human oxytocin. In another embodiment, the oxytocin peptide may be an analog or derivative of human oxytocin.

[0039] As used herein, "analog" or "derivative" refers to any peptide similar to naturally occurring oxytocin, in which one or more amino acids are substituted, deleted, or inserted. This term also refers to any peptide in which one or more amino acids (e.g., one, two, or three amino acids) are modified, for example, by chemical modification. In general, this term encompasses all peptides that exhibit oxytocin activity, but may have different potency or pharmacological profile, if desired.

[0040] It should be noted that, as used herein, the singular forms "a," "an," and "the" include plural referents unless otherwise indicated. Furthermore, as used herein, the term "comprising" and its cognates are used in their inclusive sense; that is, they are equivalent to the term "including" and its corresponding cognates.

[0041] When a range of values ​​is provided, each intervening value between the upper and lower limits of that range, and any other stated or intervening value within that stated range, is intended to be encompassed within the scope of the disclosure. For example, if a range of 1 μg to 8 μg is specified, 2 μg, 3 μg, 4 μg, 5 μg, 6 μg, and 7 μg, as well as ranges of values ​​of 1 μg or greater and 8 μg or less, are also intended to be expressly disclosed. If a range of 10 to 14% is specified, 10%, 11%, 12%, 13%, and 14% are also intended to be expressly disclosed. Furthermore, each narrower range within a stated range between any stated or intervening value and any other stated or intervening value within that stated range is encompassed within the scope of the disclosure. The upper and lower limits of these narrower ranges may independently be included in or excluded from the range, and each range in which one or both limits are included in the narrower range, or in which neither limit is included in the narrower range, is also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. When a stated range includes one or both limits, ranges excluding either or both of those included limits are also included within the disclosure.

[0042] (oxytocin peptide) Oxytocin was one of the first peptide hormones to be isolated and sequenced. Naturally occurring oxytocin is a nine-amino acid cyclic peptide hormone with two cysteine ​​residues forming a disulfide bridge between positions 1 and 6. The amino acid sequence of human oxytocin is Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly (SEQ ID NO: 1).

[0043] Processes for producing oxytocin have been reported. See, for example, U.S. Patent Nos. 2,938,891 and 3,076,797. Additionally, oxytocin is commercially available. A variety of peptide analogs and derivatives are available, and others may be contemplated for use in the present invention and may be produced according to known methods and tested for biological activity. Oxytocin analogs may include, but are not limited to, 4-threonine-1-hydroxy-deaminooxytocin, 4-serine-8-isoleucine-oxytocin, 9-deaminooxytocin, 7-D-proline-oxytocin and its deamino analogs, (2,4-diisoleucine)-oxytocin, deaminooxytocin analogs, 1-deamino-1-monocarba-E12-Tyr(OMe)]-OT (dCOMOT), 4-threonine-7-glycine-oxytocin (TG-OT), oxypressin, deamino-6-carba-oxytoxin (dC60), L-371,257, and related series of compounds containing an ortho-triglyceride phenylacetyl core such as L-374,943.Other exemplary oxytocin analogs include 4-threonine-1-hydroxy-deaminooxytocin, 9-deaminooxytocin, analogs of oxytocin containing glycine residues in place of glycinamide residues, 7-D-proline-oxytocin(2,4-diisoleucine)-oxytocin, analogs of oxytocin with natriuretic and diuretic activity, deaminooxytocin analogs; long-acting oxytocin analogs, 1-deamino-1-monocarba-E12-[Tyr(OMe )]-OT (dCOMOT), carbetocin, (1-butanoic acid-2-(O-methyl-L-tyrosine)-1-carbaoxytocin, deamino-1-monocarba-(2-O-methyltyrosine)-oxytocin [d(COMOT)]), [Thr4-Gly7]-oxytocin (TG-OT), oxypressin, Ile-conopressin, deamino-6-carba-oxytoxin (dC60), d[Lys(8)(5 / 6C-fluorescein)]VT, d[Thr(4),Lys(8)(5 / 6C-fluorescein)]VT Rescein)]VT, [HO(1)][Lys(8)(5 / 6C-fluorescein)]VT, [HO(1)][Thr(4),Lys(8)(5 / 6C-fluorescein)]VT, d[Om(8)(5 / 6C-fluorescein)]VT, d[Thr(4),Om(8)(5 / 6C-fluorescein)]VT, [HO(1)][Om(8)(5 / 6C-fluorescein)]VT, [HO(1)][Thr(4),Om(8)(5 / 6C-fluorescein)]VT, and 1-deamino-oxytocin (residue Examples of suitable oxytocin analogs include desamino-oxytocin analogs (in which the disulfide bridge between 1 and 6 is replaced by a thioether) and desamino-oxytocin analogs (in which the disulfide bond is replaced by a diselenide, ditelluride, telluroseleno, tellurosulfide, or selenosulfide bond) (e.g., the peptide analogs of oxytocin described in PCT Patent Application WO 2011 / 120,071, incorporated herein by reference). Peptides for use in the present invention may be naturally occurring peptide sequences or peptides obtainable by partial substitution, addition, or deletion of amino acids within a naturally occurring peptide sequence.The peptides can be chemically modified, for example, by amidation of the carboxyl terminus (-NH), use of D-amino acids in the peptide, incorporation of small non-peptidyl moieties, and modification of the amino acids themselves (e.g., alkylation or esterification of the side chain R group). Such analogs, derivatives, and fragments should substantially retain the desired biological activity of the native oxytocin peptide. In some embodiments, the oxytocin analog is 4-serine-8-isoleucine-oxytocin or 9-deaminooxytocin. In some embodiments, the oxytocin analog is carbetocin. The present disclosure also encompasses other known oxytocin analogs, such as the peptidic oxytocin receptor agonists described in PCT Patent Application WO2012 / 042371 and Wisniewski et al., J. Med. Chem. 2014, 57:5306-5317 (the entire contents of which are incorporated herein by reference). In some embodiments, the oxytocin analog is a compound selected from Compound Nos. 1-65 listed in Tables 1-3 of Wisniewski et al., J Med Chem. 2014, 57:5306-5317. In some embodiments, the oxytocin analog is selected from the group consisting of Compound No. 31 ([2-ThiMeGly7]dOT), Compound No. 47 (Carba-6-[Phe2,BuGly7]dOT), Compound No. 55 (Carba-6-[3-MeBzlGly7]dOT), and Compound No. 57 (Carba-1-[4-FBzlGly7]dOT, also known as merotocin).

[0044] In some embodiments, oxytocin or an oxytocin analog is isotopically labeled by having one or more atoms replaced with an isotope having a different atomic mass. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen (e.g., 2 H and 3 H), isotopes of carbon (e.g., 13 C and 14 C), isotopes of nitrogen (e.g., 15N), isotopes of oxygen (e.g., 18 O and 17 O), isotopes of phosphorus (e.g., 31 P and 32 P), isotopes of fluorine (e.g., 18 F), isotopes of chlorine (e.g., 36 Cl) and isotopes of sulfur (e.g., 35 S). Isotopically labeled compounds may be administered to one or more subjects according to conventional techniques and then detected to provide useful diagnostic and / or therapeutic management data. Furthermore, isotopically labeled compounds may be administered to one or more subjects in need thereof to provide therapeutically beneficial absorption, distribution, metabolism, and / or excretion profiles. All isotopic variations of oxytocin peptides, e.g., human oxytocin, or analogs or derivatives thereof, whether radioactive or not, are contemplated.

[0045] In some embodiments, the oxytocin peptide is human oxytocin consisting of Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly (SEQ ID NO: 1).

[0046] The "International Unit" (IU, UI, or IE) is an internationally accepted unit of activity used to quantify vitamins, hormones, and vaccines. The International Unit defines the amount of a substance that provides a unit of activity measured using a defined biological assay to standardize preparations from multiple raw materials. Similarly, the USP unit is a defined dosage unit established by the United States Pharmacopoeia in cooperation with the U.S. Food and Drug Administration to ensure the identity, strength, quality, purity, and consistency of drug products. Generally, the USP unit is equivalent to the International Unit due to attempts at harmonization. By convention, in the case of oxytocin, one unit of activity is usually defined as equivalent to approximately 2 micrograms of synthetic oxytocin peptide; or 1 mg is equivalent to 500 units (Stedman's Medical Dictionary). Thus, as used herein, one "IU" or one "International Unit" of oxytocin peptide is the amount of oxytocin peptide that has the same biological activity or produces the same level of biological effect (e.g., contractile response in rat uterine strips) as approximately 2 micrograms of the synthetic peptide. The less active the analogue, the more substance will be required to achieve the same level of biological effect.The measurement of drug efficacy is well known to those skilled in the art and can include either in vitro or in vivo assays using synthetic oxytocin as a reference.Atke and Vilhardt Acta Endocrinol 1987:115(1):155-60;Engstrom et al., Eur J Pharmacol 1998:355(2-3):203-10.

[0047] (Magnesium-containing oxytocin peptide preparation) In one embodiment, the present invention provides magnesium-containing oxytocin peptide formulations and their use in the treatment of pain.

[0048] Magnesium is involved in many aspects of life and health (e.g., energy production, oxygen uptake, central nervous system function, electrolyte balance, glucose metabolism, and muscle activity). Magnesium has also been found to be clinically effective in reducing pain, including muscle and nerve pain. Magnesium salts have been found to be analgesic when administered intravenously and when applied directly to the spinal cord in rats and humans. The mechanisms underlying these effects are unclear, but likely involve either noncompetitive blockade of N-methyl D-aspartate (NMDA) neurotransmitter receptors or increased affinity of oxytocin receptor action as an allosteric modulator, or both.

[0049] Oxytocin is known to treat headaches and craniofacial pain in humans and rats, and is particularly effective in treating chronic pain in rats where oxytocin receptors are overexpressed when administered intranasally to the upper limbs. However, it has been observed that the analgesic effect of oxytocin in treating headaches, such as migraines, in human patients does not occur immediately after administration. Rather, an initial period of up to 2 hours is required for significant analgesia to occur, and 4 hours is required for maximum analgesic effect to be reached, although the patient continues to suffer from pain during this initial period. The present inventors have surprisingly found that co-administration of oxytocin with magnesium salts can result in an unexpected synergistic reduction in pain intensity, as well as a faster onset and longer duration of analgesic effect.

[0050] Thus, provided are compositions comprising an oxytocin peptide and a magnesium salt, wherein the oxytocin peptide and the magnesium salt are present in amounts that provide synergistic analgesia when used in the treatment of pain. When used to treat pain in a subject in need thereof, the compositions can provide one or more of the following results: (i) an overall analgesic or analgesic effect (a reduction in pain intensity and / or sensitivity to painful stimuli (allodynia and / or hyperalgesia) that exceeds the sum of the analgesic or analgesic effects of equivalent amounts of the oxytocin peptide and the magnesium salt administered individually; (ii) a reduction in the frequency of pain experienced by the subject that exceeds the sum of the reductions in pain frequency caused by equivalent amounts of the oxytocin peptide and the magnesium salt administered individually; (iii) a more rapid onset of analgesia or analgesia than any equivalent amount of any analgesic administered alone; and / or (iv) a longer-lasting analgesic or analgesic effect than any equivalent amount of any analgesic administered alone. In some embodiments, the composition comprises an oxytocin peptide and a magnesium salt, wherein the oxytocin peptide and the magnesium salt are present in an amount that effects one or more of the results (i)-(iv).

[0051] The relative ratio of oxytocin peptide and magnesium in magnesium-containing oxytocin peptide preparations is important when achieving optimal and synergistic analgesia.The optimal amount of oxytocin peptide and magnesium salt can depend on other factors such as specific pain type, desired synergistic effect type and administration route.For example, the amount of magnesium can be important for faster analgesia to occur; the amount of oxytocin can be important for longer-lasting analgesia, and the relative ratio of oxytocin and magnesium can be important for maximally reducing pain intensity.

[0052] In some embodiments, the magnesium-containing oxytocin peptide formulation or composition is a liquid formulation containing about 0.01 mg / mL to about 16 mg / mL of oxytocin peptide. In some embodiments, the magnesium-containing oxytocin peptide formulation or composition is about 0.01 mg / mL to about 12 mg / mL, about 0.05 mg / mL to about 16 mg / mL, about 0.1 mg / mL to about 12 mg / mL, about 0.1 mg / mL to about 8 mg / mL, about 0.1 mg / mL to about 4 mg / mL, about 0.1 mg / mL to about 2 mg / mL, about 0.1 mg / mL to about 1.6 mg / mL, about 0.1 mg / mL to about 1.2 mg / mL, or about 0.1 mg / mL to about 1 mg / mL. mg / mL, about 0.1 mg / mL to about 0.8 mg / mL, about 0.1 mg / mL to about 0.4 mg / mL, about 0.1 mg / mL to about 0.3 mg / mL, about 0.2 mg / mL to about 16 mg / mL, about 0.2 mg / mL to about 12 mg / mL, Approximately 0.2 mg / mL to approximately 10 mg / mL, approximately 0.2 mg / mL to approximately 8 mg / mL, approximately 0.2 mg / mL to approximately 6 mg / mL, approximately 0.2 mg / mL to approximately 4 mg / mL, approximately 0.2 mg / mL to approximately 2 mg / mL, approximately 0.2 mg / mL to approximately 1. 6mg / mL, about 0.2mg / mL to about 1.2mg / mL, about 0.2mg / mL to about 1mg / mL, about 0.2mg / mL to about 0.8mg / mL, about 0.2mg / mL to about 0.6mg / mL, about 0.2mg / mL to about 0.4mg / m L, about 0.2 mg / mL to about 0.3 mg / mL, about 0.3 mg / mL to about 16 mg / mL, about 0.3 mg / mL to about 12 mg / mL, about 0.3 mg / mL to about 10 mg / mL, about 0.3 mg / mL to about 8 mg / mL, about 0.3 mg / mL mL to about 4 mg / mL, about 0.3 mg / mL to about 3 mg / mL, about 0.3 mg / mL to about 1 mg / mL, about 0.3 mg / mL to about 0.5 mg / mL, about 0.5 mg / mL to about 16 mg / mL, about 0.5 mg / mL to about 10 mg / mL, about 0.5 mg / mL to about 5 mg / mL, about 0.5 mg / mL to about 1 mg / mL, about 1 mg / mL to about 16 mg / mL, about 1 mg / mL to about 10 mg / mL, or about 1 mg / mL to about 5 mg / mL of oxytocin peptide.In a preferred embodiment, the magnesium-containing oxytocin peptide formulation or composition contains about 0.1 mg / mL to about 2 mg / mL, about 0.15 mg / mL to about 1.5 mg / mL, or about 0.2 mg / mL to about 1.2 mg / mL of oxytocin peptide. In one embodiment, the oxytocin peptide is human oxytocin consisting of Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly (SEQ ID NO: 1).

[0053] In some embodiments, the magnesium-containing oxytocin peptide formulation or composition is a liquid formulation containing about 5 IU / mL to about 8000 IU / mL of oxytocin peptide. In some embodiments, the magnesium-containing oxytocin peptide formulation or composition contains about 500 IU / mL to about 6000 IU / mL, about 25 IU / mL to about 8000 IU / mL, about 50 IU / mL to about 6000 IU / mL, about 50 IU / mL to about 4000 IU / mL, about 50 IU / mL to about 2000 IU / mL, about 50 IU / mL to about 1000 IU / mL, about 50 IU / mL to about 800 IU / mL, about 50 IU / mL to about 600 IU / mL, about 50 IU / mL to about 500 IU / mL, or about 50 IU / mL to about 600 IU / mL. IU / mL~about 400IU / mL, about 50IU / mL~about 200IU / mL, about 50IU / mL~about 150IU / mL, about 100IU / mL~about 8000IU / mL, about 100IU / mL~about 6000IU / mL, about 100IU / mL~about 5000 IU / mL, about 100IU / mL to about 4000IU / mL, about 100IU / mL to about 3000IU / mL, about 100IU / mL to about 2000IU / mL, about 100IU / mL to about 1000IU / mL, about 100IU / mL to about 800IU / mL, about 1 00IU / mL~about 600IU / mL, about 100IU / mL~about 500IU / mL, about 100IU / mL~about 400IU / mL, about 100IU / mL~about 300IU / mL, about 100IU / mL~about 200IU / mL, about 100IU / mL~about 15 0IU / mL, about 150IU / mL to about 8000IU / mL, about 150IU / mL to about 6000IU / mL, about 150IU / mL to about 5000IU / mL, about 150IU / mL to about 4000IU / mL, about 150IU / mL to about 2000IU / mL, Contains about 150 IU / mL to about 1500 IU / mL, about 150 IU / mL to about 500 IU / mL, about 150 IU / mL to about 250 IU / mL, about 250 IU / mL to about 8000 IU / mL, about 250 IU / mL to about 5000 IU / mL, about 250 IU / mL to about 2500 IU / mL, about 250 IU / mL to about 500 IU / mL, about 500 IU / mL to about 8000 IU / mL, about 500 IU / mL to about 5000 IU / mL, or about 500 IU / mL to about 2500 IU / mL of oxytocin peptide.In a preferred embodiment, the magnesium-containing oxytocin peptide formulation or composition contains about 50 IU / mL to about 1000 IU / mL, about 75 IU / mL to about 750 IU / mL, or about 100 IU / mL to about 600 IU / mL of oxytocin peptide. In one embodiment, the oxytocin peptide is human oxytocin consisting of Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly (SEQ ID NO: 1).

[0054] Any magnesium salt (e.g., water-soluble magnesium salt) may be used to provide magnesium in the magnesium-containing oxytocin peptide formulation of the present invention, as long as it provides synergistic analgesia when used to treat pain. The magnesium salt used in the magnesium-containing oxytocin peptide formulation can be selected based on several factors (e.g., the amount of free magnesium ions that can be delivered when the formulation is administered, the solubility of the magnesium salt in the liquid formulation medium, the acidity / basicity of the counterion, and / or the dissociation constant of the salt). For example, in a liquid formulation, the magnesium salt must be sufficiently soluble in the liquid medium to deliver the magnesium ion concentration required to provide synergistic analgesia with the oxytocin peptide. When selecting a magnesium salt, other factors (e.g., compatibility with other substances in the formulation and the ability of the counterion to perform other functions in the formulation) can also be considered. For example, magnesium citrate is sufficiently soluble in aqueous solution to provide a desired amount of magnesium or a desired magnesium ion concentration; citrate can be pharmaceutically acceptable; citrate can be part of a buffer; magnesium citrate can add a pleasant flavor to the formulation.The magnesium ion in the magnesium-containing oxytocin peptide formulation can be provided by using one or more magnesium salts.The magnesium salt in the magnesium-containing oxytocin peptide formulation can be the magnesium salt that is first used when preparing the magnesium-containing oxytocin peptide formulation, or can be formed in situ during the preparation of the magnesium-containing oxytocin peptide formulation.For example, magnesium chloride can be first used in the preparation of the formulation; magnesium citrate can be formed in situ when adding citric acid to the formulation.In such a case, the magnesium ion in the magnesium-containing oxytocin peptide formulation is provided by both magnesium chloride and magnesium citrate.

[0055] The magnesium salt used in the magnesium-containing oxytocin peptide formulations described herein can be obtained from commercial sources or prepared according to methods known in the art.For example, magnesium citrate can be prepared according to the procedures described in Staszczuk P et al., Physicochem Probl Mineral Proc 37:149-158 (2003), U.S. Patent No. 1,936,364 and U.S. Patent No. 2,260,004.

[0056] Thus, in some embodiments, the magnesium-containing oxytocin peptide formulation or composition comprises magnesium citrate. The concentration of the magnesium salt is determined by the weight concentration or percentage of the salt, or the Mg or Mg provided by the salt. 2+ The magnesium concentration may be measured by the weight percent (w / v) or equivalent concentration. For liquid formulations, weight percent (w / v) refers to the amount of magnesium salt in grams in 100 mL of solution. For example, a 10% (w / v) magnesium citrate solution contains 10 g of magnesium citrate in 100 mL of solution. When other magnesium salts are used in place of magnesium citrate, the magnesium concentrations contemplated for use in the methods and formulations described herein are equivalent to the concentrations produced by using magnesium citrate in the amounts recited herein.

[0057] The amount of magnesium present in the above formulations is expressed as a weight percent (w / v) (magnesium or Mg per 100 mL of solution). 2+ grams of magnesium or Mg 2+ (milligrams of magnesium or Mg per liter of solution) or molar concentration 2+ "M" defined as moles of magnesium or Mg per liter of solution 2+It can also be expressed as "mM," defined as millimoles of magnesium or Mg, provided by a solution of magnesium citrate (anhydrous magnesium citrate dibasic, molecular weight: 214.4). 2+ The equivalent weight of (atomic weight: 24.3) can be calculated as follows: [%Mg 2+ (w / v)] = (24.3 / 214.4) * [% Mg citrate (w / v)] = 0.113 * [% Mg citrate (w / v)] mM Mg 2+ =411.5 * [%Mg 2+ (w / v)] = 46.6 * [% Mg citrate (w / v)] mg / mL Mg 2+ =10 * [%Mg 2+ (w / v)] = 0.0243 * [mM Mg 2+ ]=1.13 * [% Mg citrate (w / v)]

[0058] Table A shows exemplary concentrations of magnesium citrate in weight percent (w / v) and magnesium or Mg in weight percent (w / v), mg / mL, and mM. 2+ The portions correspond to the serving size. [Table A]

[0059] In some embodiments, the magnesium-containing oxytocin peptide formulation or composition is a liquid formulation containing magnesium citrate in an amount providing from about 1 mg / mL to about 30 mg / mL of magnesium. In some embodiments, the composition provides from about 1 mg / mL to about 30 mg / mL of magnesium ions (Mg 2+The composition comprises magnesium citrate in an amount to provide a saturation concentration of about 11 mg / mL to about 15 mg / mL of magnesium or magnesium ion. The amount of magnesium ion can be in any form, for example, as a solvate or coordination complex in a liquid formulation, or as a crystalline lattice in a solid formulation. In some embodiments, the composition comprises one or more magnesium salts selected from the group consisting of magnesium chloride, magnesium citrate, magnesium sulfate, and magnesium acetate in an amount to provide about 11 mg / mL to about 15 mg / mL or about 400 mM to about 600 mM of magnesium or magnesium ion. In some embodiments, the composition comprises magnesium chloride and / or magnesium citrate in an amount to provide about 11 mg / mL to about 15 mg / mL or about 400 mM to about 600 mM of magnesium or magnesium ion. In some embodiments, the composition comprises magnesium citrate in an amount to provide about 11 mg / mL to about 15 mg / mL of magnesium or magnesium ion. In some embodiments, the composition contains about 10 mg / mL to about 250 mg / mL of magnesium citrate (e.g., anhydrous dibasic magnesium citrate, MW 214.4). In some embodiments, the composition contains about 1% to about 25% (w / v) of magnesium citrate (e.g., anhydrous dibasic magnesium citrate, MW 214.4). In some embodiments, the composition comprises about 1% to about 15%, about 1% to about 15%, about 1% to about 12%, about 1% to about 10%, about 1% to about 8%, about 1% to about 5%, about 2% to about 15%, about 3% to about 15%, about 4% to about 15%, about 4% to about 14%, about 4% to about 12%, about 4% to about 10%, about 4% to about 8%, about 5% to about 15%, about 5% to about 12%, about 5% to about 10%, about 8% to about 15%, about 8% to about 12%, about 8% to about 10%, about 10% to about 15%, about 10% to about 14%, about 10% to about 12%, about 11% to about 15%, or about 11% to about 13% (w / v) magnesium citrate. In some embodiments, the composition comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% (w / v) magnesium citrate.In some embodiments, the magnesium-containing oxytocin peptide formulation or composition is a liquid formulation containing about 0.01 mg / mL to about 16 mg / mL (preferably about 0.1 mg / mL to about 2 mg / mL, more preferably about 0.15 mg / mL to about 1.5 mg / mL or about 0.33 mg / mL) of oxytocin peptide and about 1% to about 25% (preferably about 10% to about 14% or about 12%) (w / v) of magnesium citrate. In some embodiments, the magnesium-containing oxytocin peptide formulation or composition is a liquid formulation containing about 0.5 IU / mL to about 8000 IU / mL (preferably about 50 IU / mL to about 1000 IU / mL, more preferably about 75 IU / mL to about 225 IU / mL or about 150 IU / mL) of oxytocin peptide and about 1% to about 25% (preferably about 10% to about 14% or about 12%) (w / v) of magnesium citrate.

[0060] In some embodiments, the composition contains magnesium chloride in an amount providing about 11 mg / mL to about 15 mg / mL of magnesium or magnesium ions. In some embodiments, the composition contains about 10 mg / mL to about 250 mg / mL of magnesium chloride (e.g., magnesium chloride hexahydrate, MW 203.3). In some embodiments, the composition contains about 1% to about 25% (w / v) magnesium chloride hexahydrate (MgCl2·6H2O, MW 203.3). In some embodiments, the composition comprises about 1% to about 15%, about 1% to about 15%, about 1% to about 12%, about 1% to about 10%, about 1% to about 8%, about 1% to about 5%, about 2% to about 15%, about 3% to about 15%, about 4% to about 15%, about 4% to about 14%, about 4% to about 12%, about 4% to about 10%, about 4% to about 8%, about 5% to about 15%, about 5% to about 12%, about 5% to about 10%, about 8% to about 15%, about 8% to about 12%, about 8% to about 10%, about 10% to about 15%, about 10% to about 14%, about 10% to about 12%, about 11% to about 15%, or about 11% to about 13% (w / v) magnesium chloride hexahydrate. In some embodiments, the composition contains about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% (w / v) magnesium chloride hexahydrate. In some embodiments, the magnesium-containing oxytocin peptide formulation or composition is a liquid formulation containing about 0.01 mg / mL to about 16 mg / mL (preferably, about 0.1 mg / mL to about 2 mg / mL, more preferably, about 0.15 mg / mL to about 1.5 mg / mL or about 0.33 mg / mL) oxytocin peptide and about 1% to about 25% (preferably, about 8% to about 12% or about 10%) (w / v) magnesium chloride hexahydrate.In some embodiments, the magnesium-containing oxytocin peptide formulation or composition is a liquid formulation containing about 0.5 IU / mL to about 8000 IU / mL (preferably, about 50 IU / mL to about 1000 IU / mL, more preferably, about 75 IU / mL to about 225 IU / mL or about 150 IU / mL) of oxytocin peptide and about 1% to about 25% (preferably, about 8% to about 12% or about 10%) (w / v) of magnesium chloride hexahydrate.

[0061] In some embodiments, the magnesium-containing oxytocin peptide formulation or composition comprises one or more magnesium salts selected from the group consisting of magnesium citrate, magnesium chloride, magnesium sulfate, magnesium acetate, magnesium lactate, magnesium stearate, magnesium oxide, magnesium carbonate, magnesium glycinate, magnesium maltate, magnesium taurate, magnesium gluconate, magnesium succinate, and magnesium pyrophosphate. In some embodiments, the magnesium-containing oxytocin peptide formulation or composition is a liquid formulation comprising a magnesium salt (e.g., magnesium citrate or magnesium chloride) in an amount providing from about 1 mg / mL to about 30 mg / mL of magnesium. In some embodiments, the composition provides from about 1 mg / mL to about 30 mg / mL of magnesium ion (Mg 2+ In some embodiments, the magnesium-containing oxytocin peptide formulation or composition contains about 1 mg / mL to about 30 mg / mL of magnesium or magnesium ions (Mg 2+In some embodiments, the composition comprises one or more magnesium salts (e.g., magnesium citrate and / or magnesium chloride) in an amount to provide about 11 mg / mL to about 15 mg / mL of magnesium or magnesium ions. In some embodiments, the magnesium-containing oxytocin peptide formulation or composition comprises about 1 mg / mL to about 30 mg / mL (or about 3 mg / mL to about 30 mg / mL, about 4 mg / mL to about 30 mg / mL, about 5 mg / mL to about 30 mg / mL, about 8 mg / mL to about 30 mg / mL, about 10 mg / mL to about 30 mg / mL, preferably about 11 mg / mL to about 15 mg / mL, or about 13 mg / mL, or about 12 mg / mL) of magnesium or Mg. 2+ In some embodiments, the magnesium-containing oxytocin peptide formulation or composition is a liquid formulation containing about 0.01 mg / mL to about 16 mg / mL (preferably about 0.1 mg / mL to about 2 mg / mL, more preferably about 0.15 mg / mL to about 1.5 mg / mL or about 0.33 mg / mL) of oxytocin peptide and a magnesium salt (e.g., magnesium citrate or magnesium chloride) in an amount that provides a therapeutic effect. In some embodiments, the magnesium-containing oxytocin peptide formulation or composition contains about 1 mg / mL to about 30 mg / mL (preferably about 11 mg / mL to about 15 mg / mL, or about 13 mg / mL, or about 12 mg / mL) of magnesium or Mg 2+ The oxytocin peptide formulation or composition is a liquid formulation containing about 5 IU / mL to about 8000 IU / mL (preferably about 50 IU / mL to about 1000 IU / mL, more preferably about 75 IU / mL to about 750 IU / mL or about 150 IU / mL) of oxytocin peptide and one or more magnesium salts (e.g., magnesium citrate and / or magnesium chloride) in an amount that provides a therapeutic effect. In some embodiments, the magnesium-containing oxytocin peptide formulation or composition contains about 50 mM to about 1200 mM (or about 100 mM to about 1200 mM, about 150 mM to about 1200 mM, about 200 mM to about 1200 mM, about 300 mM to about 1200 mM, about 400 mM to about 1200 mM, preferably about 400 mM to about 600 mM or about 500 mM) of magnesium or Mg.2+ and one or more magnesium salts (e.g., magnesium citrate and / or magnesium chloride).

[0062] The relative amounts of oxytocin peptide and magnesium or magnesium ions in the magnesium-containing oxytocin peptide formulations or compositions described herein may be defined by weight ratio or molar ratio. The weight ratio of the amount of oxytocin peptide in a formulation or composition to the amount of magnesium or the amount of magnesium ions provided by a magnesium salt is referred to as the "OT / Mg(w) ratio." For example, in a magnesium-containing oxytocin peptide formulation or composition having an OT / Mg(w) ratio of about 1:40, for each 1 mg of oxytocin peptide present in the formulation or composition, the magnesium salt present in the formulation or composition provides about 40 mg of magnesium or magnesium ions. The molar ratio of the amount of oxytocin peptide in a formulation or composition to the amount of magnesium or the amount of magnesium ions provided by a magnesium salt is referred to as the "OT / Mg(m) ratio." For example, in a magnesium-containing oxytocin peptide formulation or composition having an OT / Mg(m) ratio of about 1:1600, for every 1 μmol of oxytocin peptide present in the formulation or composition, the magnesium salt present in the formulation or composition provides about 1600 μmol of magnesium or magnesium ions.

[0063] In some embodiments, a magnesium-containing oxytocin peptide formulation or composition is provided comprising an oxytocin peptide and a magnesium salt, wherein the formulation or composition has an OT / Mg(w) ratio of about 1:1 to about 1:1000. In some embodiments, the formulation or composition has an OT / Mg(w) ratio of about 1:2 to about 1:200. In some preferred embodiments, the formulation or composition has an OT / Mg(w) ratio of about 1:30, about 1:35, about 1:40, about 1:45, or about 1:50. In some embodiments, the formulation or composition is about 1:2 to about 1:1000, about 1:2 to about 1:800, about 1:2 to about 1:500, about 1:2 to about 1:250, about 1:2 to about 1:150, about 1:2 to about 1:100, about 1:2 to about 1:80, about 1:2 to about 1:60, about 1:2 to about 1:50, about 1:2 to about 1:40, about 1:2 to about 1:30, about 1:2 to about 1:20, about 1:2 to about 1:10, about 1:2 to about 1:5, about 1:2 to about 1:50, about 1:2 to about 1:60, about 1:2 to about 1:50, about 1:2 to about 1:40, about 1:2 to about 1:30, about 1:2 to about 1:20, about 1:2 to about 1:10, about 1:2 to about 1:5 ... :5 to about 1:1000, about 1:5 to about 1:800, about 1:5 to about 1:500, about 1:5 to about 1:200, about 1:5 to about 1:100, about 1:5 to about 1:80, about 1:5 to about 1:60, about 1:5 to about 1:50, about 1:5 to about 1:40, about 1:5 to about 1:30, about 1:5 to about 1:20, about 1:5 to about 1:10, about 1:10 to about 1:1000, about 1:10 to about 1:800, about 1:10 to about 1:500, about 1:10 to about 1:200 , about 1:10 to about 1:100, about 1:10 to about 1:80, about 1:10 to about 1:60, about 1:10 to about 1:50, about 1:10 to about 1:40, about 1:10 to about 1:30, about 1:10 to about 1:20, about 1:20 to about 1:1000, about 1:20 to about 1:800, about 1:20 to about 1:500, about 1:20 to about 1:200, about 1:20 to about 1:100, about 1:20 to about 1:80, about 1:20 to about 1:70, about 1:20 to about 1:60, About 1:20 to about 1:50, about 1:20 to about 1:40, about 1:20 to about 1:30, about 1:30 to about 1:1000, about 1:30 to about 1:800, about 1:30 to about 1:500, about 1:30 to about 1:200, about 1:30 to about 1:100, about 1:30 to about 1:80, about 1:30 to about 1:70, about 1:30 to about 1:60, about 1:30 to about 1:50, about 1:30 to about 1:40, about 1:35 to about 1:45, about 1:40 to about 1:1000,Approximately 1:40 to approximately 1:800, approximately 1:40 to approximately 1:500, approximately 1:40 to approximately 1:200, approximately 1:40 to approximately 1:100, approximately 1:40 to approximately 1:80, approximately 1:40 to approximately 1:70, approximately 1:40 to approximately 1:60, approximately 1:40 to approximately 1:50, approximately 1:50 to approximately 1:1000, approximately 1:50 to approximately 1:800, approximately 1:50 to approximately 1:500, approximately 1:50 to approximately 1:200, approximately 1:50 to approximately 1:100, approximately 1:50 to approximately 1:90, approximately 1:50 to approximately 1:80, approximately 1:50 to approximately 1:70, approximately 1:50 to approximately 1:60, approximately 1:60 to approximately 1:1000, approximately 1:60 to approximately 1:800, approximately 1:60 to approximately 1:500, approximately 1: 60 to approximately 1:200, approximately 1:60 to approximately 1:100, approximately 1:60 to approximately 1:90, approximately 1:60 to approximately 1:80, approximately 1:60 to approximately 1:70, approximately 1:80 to approximately 1:1000, approximately 1:80 to approximately 1:800, approximately 1:80 to approximately 1:500, approximately 1:80 to approximately 1:200, approximately 1:80 to approximately 1:100, approximately 1: The OT / Mg(w) ratio is 100 to about 1:1000, about 1:100 to about 1:800, about 1:100 to about 1:500, about 1:100 to about 1:200, about 1:200 to about 1:1000, about 1:200 to about 1:800, about 1:200 to about 1:500, or about 1:500 to about 1:1000. In one embodiment, the oxytocin peptide is human oxytocin consisting of Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly (SEQ ID NO: 1), and / or the magnesium salt thereof is magnesium citrate.

[0064] In some embodiments, a magnesium-containing oxytocin peptide formulation or composition is provided comprising an oxytocin peptide and a magnesium salt, wherein the formulation or composition has an OT / Mg(m) ratio of about 1:40 to about 1:40,000. In some embodiments, the formulation or composition has an OT / Mg(m) ratio of about 1:80 to about 1:8000. In some preferred embodiments, the formulation or composition has an OT / Mg(m) ratio of about 1:1200, about 1:1400, about 1:1600, about 1:1800, or about 1:2000. In some embodiments, the formulation or composition has a viscosity of about 1:80 to about 1:40,000, about 1:80 to about 1:30,000, about 1:80 to about 1:20,000, about 1:80 to about 1:10,000, about 1:80 to about 1:7,500, about 1:80 to about 1:5,000, about 1:80 to about 1:3,000, about 1:80 to about 1:2,000, about 1:80 to about 1:1,600, about 1:80 to about 1:1,200, about 1:80 to about 1:800 , about 1:80 to about 1:400, about 1:80 to about 1:200, about 1:200 to about 1:40000, about 1:200 to about 1:30000, about 1:200 to about 1:20000, about 1:200 to about 1:10000, about 1:200 to about 1:5000, about 1:200 to about 1:3000, about 1:200 to about 1:2400, about 1:200 to about 1:2000, about 1:200 to about 1:1600, about 1:200 to about 1:1200, about 1:200 to approximately 1:800, approximately 1:200 to approximately 1:400, approximately 1:400 to approximately 1:40000, approximately 1:400 to approximately 1:30000, approximately 1:400 to approximately 1:20000, approximately 1:400 to approximately 1:8000, approximately 1:400 to approximately 1:4000, approximately 1:400 to approximately 1:3000, approximately 1:400 to approximately 1:2400, approximately 1:400 to approximately 1:2000, approximately 1:400 to approximately 1:1600, approximately 1:400 to approximately 1:1200, approximately 1 :400 to approximately 1:800, approximately 1:800 to approximately 1:40000, approximately 1:800 to approximately 1:30000, approximately 1:800 to approximately 1:20000, approximately 1:800 to approximately 1:10000, approximately 1:800 to approximately 1:5000, approximately 1:800 to approximately 1:3000, approximately 1:800 to approximately 1:2400, approximately 1:800 to approximately 1:2000, approximately 1:800 to approximately 1:1600, approximately 1:800 to approximately 1:1200, approximately 1:1200 to approximately 1:40000,Approximately 1:1200 to approximately 1:30000, approximately 1:1200 to approximately 1:20000, approximately 1:1200 to approximately 1:10000, approximately 1:1200 to approximately 1:5000, approximately 1:1200 to approximately 1:4000, approximately 1:1200 to approximately 1:3000, approximately 1:1200 to approximately 1:2400, approximately 1:1200 to approximately 1:2000, approximately 1:1200 to approximately 1:1600, approximately 1:1400 to approximately 1:1800, approximately 1:1600 to approximately 1:40000, approximately 1:1600 to approximately 1:3000 0, about 1:1600 to about 1:20000, about 1:1600 to about 1:10000, about 1:1600 to about 1:5000, about 1:1600 to about 1:3000, about 1:1600 to about 1:2400, about 1:1600 to about 1:2000, about 1:2000 to about 1:40000, about 1:2000 to about 1:30000, about 1:2000 to about 1:20000, about 1:2000 to about 1:10000, about 1:2000 to about 1:5000, about 1:2000 to about 1: 4000, approx. 1:2000 to approx. 1:3000, approx. 1:2000 to approx. 1:2400, approx. 1:2400 to approx. 1:40000, approx. 1:2400 to approx. 1:30000, approx. 1:2400 to approx. 1:20000, approx. 1:2400 to approx. 1:10000, approx. 1:2400 to approx. 1:5000, approx. 1:2400 to approx. 1:4000, approx. 1:2400 to approx. 1:3000, approx. 1:3000 to approx. 1:40000, approx. 1:3000 to approx. 1:30000, approx. 1:3000 to having an OT / Mg(m) ratio of about 1:20,000, about 1:3,000 to about 1:10,000, about 1:3,000 to about 1:4,000, about 1:4,000 to about 1:40,000, about 1:4,000 to about 1:30,000, about 1:4,000 to about 1:20,000, about 1:4,000 to about 1:10,000, about 1:8,000 to about 1:40,000, about 1:8,000 to about 1:30,000, about 1:8,000 to about 1:20,000, or about 1:10,000 to about 1:40,000. In one embodiment, the oxytocin peptide is human oxytocin consisting of Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly (SEQ ID NO: 1), and / or the magnesium salt is magnesium citrate.

[0065] In some embodiments, magnesium-containing oxytocin peptide formulations or compositions comprising oxytocin peptide and magnesium salts further comprise one or more pharmaceutically acceptable carriers (thus constituting a pharmaceutical composition) and optionally other components (e.g., excipients, vehicles, emulsifiers, stabilizers, preservatives, buffers, and / or other additives that may enhance stability, delivery, absorption, half-life, efficacy, pharmacokinetics and / or pharmacodynamics, reduce adverse side effects, or provide other benefits for pharmaceutical use). Exemplary excipients include solubilizers, surfactants, and chelating agents. For example, the formulation may include methyl-β-cyclodextrin (Me-β-CD), edetate disodium, arginine, sorbitol, NaCl, methylparaben sodium (MP), propylparaben sodium (PP), chlorobutanol (CB), benzyl alcohol, zinc chloride, ethyl alcohol, didecanoyl L-α-phosphatidylcholine (DDPC), polysorbate, lactose, citrate, tartrate, acetate, and / or phosphate.

[0066] Liquid carriers include, but are not limited to, water, saline, aqueous dextrose, and glycols, particularly for isotonic solutions. The carriers may also be selected from a variety of oils, including those of petroleum, animal, vegetable, or synthetic origin (e.g., peanut oil, olive oil, soybean oil, mineral oil, sesame oil, etc.). Suitable pharmaceutical excipients include, but are not limited to, starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, and the like. The compositions may be subjected to conventional pharmaceutical processes, such as sterilization, and may contain conventional pharmaceutical additives (e.g., preservatives, stabilizers, reducing agents, antioxidants, chelating agents, wetting agents, emulsifiers, dispersing agents, gelling agents, salts for adjusting osmotic pressure, buffers, etc.). The liquid carrier may be hypotonic or isotonic with respect to body fluids and may have a pH within the range of 3.5 to 8.5. The use of additives in the preparation of peptide and / or protein-based compositions, particularly pharmaceutical compositions, is well known in the art. In some embodiments, the composition has a pH of about 2 to about 7. In some embodiments, the composition has a pH of about 4 to about 7. In a preferred embodiment, the pH of the formulation / composition is about 4.5.

[0067] (E) mucolytic or mucus-clearing agents; (F) ciliostatic agents; (G) membrane permeability enhancers; (H) modulators of epithelial junctional physiology (e.g., nitric oxide (NO) stimulators, chitosan and chitosan derivatives); (I) vasodilators; (J) selective transport enhancers; and (K) stabilizing delivery vehicles, carriers, carriers, or complexing species that are effectively combined with, associated with, contained within, encapsulated, or bound to the oxytocin peptide to stabilize the active agent for enhanced mucosal delivery. The membrane permeation enhancers in group (G) can be (i) surfactants, (ii) bile salts, (iii) phospholipid or fatty acid additives, mixed micelles, liposomes or carriers, (iv) alcohols, (v) enamines, (iv) NO donor compounds, (vii) long-chain amphiphilic molecules, (viii) small molecule hydrophobic permeation enhancers; (ix) sodium or salicylic acid derivatives; (x) glycerol esters of acetoacetic acid, (xi) cyclodextrins or beta-cyclodextrin derivatives, (xii) medium-chain fatty acids, (xiii) chelating agents, (xiv) amino acids or salts thereof, (xv) N-acetyl amino acids or salts thereof, (xvi) enzymes degradative of selected membrane components, (xvii) inhibitors of fatty acid synthesis, (xviii) inhibitors of cholesterol synthesis; or (xiv) any combination of the membrane permeation enhancers of (i)-(xviii). In various embodiments of the present invention, the oxytocin peptide may be combined with one, two, three, four, or more of the mucosal delivery-enhancing agents listed in (A) through (K). These mucosal delivery-enhancing agents, alone or together, may be admixed with the oxytocin peptide or otherwise combined therewith in a pharmaceutically acceptable formulation or delivery vehicle.The magnesium-containing oxytocin peptide formulations or compositions described herein may increase the bioavailability of the oxytocin peptide after delivery to a mucosal surface (e.g., the mucosal surface of the nasal cavity) of a mammalian subject.

[0068] The list of carriers and additives discussed herein is by no means complete, and one of skill in the art can select carriers and excipients from the GRAS (generally regarded as safe) list of chemicals approved in pharmaceuticals and those currently approved by the U.S. Food and Drug Administration in topical and parenteral formulations, as well as those that will be approved in the future (see also Wang et al. (1980) J. Parent. Drug Assn., 34:452-462; Wang et al. (1988) J. Parent. Sci. and Tech., 42:S4-S26).

[0069] In some embodiments, a magnesium-containing oxytocin peptide formulation or composition comprising an oxytocin peptide and a magnesium salt, wherein the oxytocin peptide and magnesium salt are present in amounts that provide synergistic analgesia when used to treat pain, further comprises one or more solvents or excipients selected from the group consisting of chlorobutanol, benzalkonium, methyl 4-hydroxybenzoate, propyl 4-hydroxybenzoate, acetic acid, citric acid, glycerol, sodium chloride, sodium monohydrogen phosphate, sorbitol, and water. In some embodiments, the magnesium-containing oxytocin peptide formulation or composition further comprises chlorobutanol, acetic acid, and water.

[0070] In some embodiments, a magnesium-containing oxytocin peptide formulation or composition comprising an oxytocin peptide and a magnesium salt further comprises a chitosan-containing excipient (e.g., ChiSys®, http: / / www.archimedespharma.com / productArchiDevChiSys.html). In some embodiments, a magnesium-containing oxytocin peptide formulation or composition further comprises about 1% of a chitosan-containing excipient. In some embodiments, chitosan glutamate may be preferred for nasal delivery due to its superior absorption-enhancing capabilities. In some embodiments, chitosan copolymer nanoparticles (e.g., nanoparticles comprising chitosan glutamate and a negatively charged polymer (e.g., pentasodium tripolyphosphate)) may be used. Thiolated chitosan (e.g., chitosan covalently modified with 2-iminothiolane) has been used in microparticles comprising insulin and reduced glutathione and may also be useful as an excipient in the magnesium-containing oxytocin peptide formulations or compositions described herein.

[0071] In some embodiments, magnesium-containing oxytocin peptide formulations or compositions comprising oxytocin peptide and magnesium salts further comprise one or more gelling agents so that the oxytocin peptide formulation forms a gel in the nasal cavity, thereby enhancing nasal absorption of the oxytocin peptide. Gelling systems useful in the formulations and methods described herein can include any known gelling system, such as chemically reactive pectin-based gelling systems (e.g., PecSys™, Archimedes Pharma) and thermoresponsive polymer gelling systems (e.g., Pluronic® F127, BASF). PecSys™ is a low-viscosity pectin-based aqueous solution delivered as a fine mist that gels upon contact with calcium ions in the nasal mucosa. Other low-methoxy pectins can also be used, for example, at a concentration of about 1%. Pluronic® F127 contains an ethylene oxide / propylene oxide block copolymer. The gelling temperature varies depending on the ratio of components and the amount of copolymer used in the final formulation. Gelling in the human nasal cavity has been demonstrated, for example, with approximately 18-20% wt / vol Pluronic® F127, as used in vitamin B12 gel supplements (EnerB, Nature's Bounty, NY) and gelling sumatriptan containing 18% wt / vol Pluronic® F127 and 0.3% wt / vol Carbopol (anionic bioadhesive polymer C934P). The monomer ratio and concentration can be adjusted for the intended oxytocin formulation to ensure gelation at 25-37°C, near the standard intranasal temperature of 34°C. If the gelation temperature is below 25°C, the formulation may gel at room temperature; if the gelation temperature is above 37°C, the formulation will not gel completely upon contact with the nasal mucosa. In some embodiments, the magnesium-containing oxytocin peptide formulation or composition may further comprise a mucoadhesive agent, such as Carbopol. The addition of a mucoadhesive agent, for example up to 0.5% Carbopol, can further reduce the gelling temperature.

[0072] In some embodiments, a magnesium-containing oxytocin peptide formulation or composition comprising an oxytocin peptide and a magnesium salt further comprises a surfactant, such as a non-ionic surfactant (e.g., polysorbate-80) and one or more buffers, stabilizers, or tonicifiers. In some embodiments, a magnesium-containing oxytocin peptide formulation or composition further comprises a propellant. The pH of the nasal spray solution is optionally about pH 3.0 to 8.5, although if desired, the pH may be adjusted to optimize delivery of charged macromolecular species (e.g., therapeutic proteins or peptides) in a substantially ionized state. The pharmaceutical solvent used may also be a slightly acidic aqueous buffer (pH 3 to 6). Suitable buffers for use in these compositions are as described above or otherwise known in the art. Other components, including preservatives, surfactants, dispersants, or gases, may be added to enhance or maintain chemical stability. Suitable preservatives include, but are not limited to, phenol, methylparaben, parabens, m-cresol, thiomersal, benzalkonium chloride, and the like. Suitable surfactants include, but are not limited to, oleic acid, sorbitan trioleate, polysorbates, lecithin, phosphotidylcholine, and various long-chain diglycerides and phospholipids. Suitable dispersing agents include, but are not limited to, ethylenediaminetetraacetic acid (EDTA). Suitable gases include, but are not limited to, nitrogen, helium, chlorofluorocarbons (CFCs), hydrofluorocarbons (HFCs), carbon dioxide, air, and the like. Suitable stabilizers and tonicifying agents include sugars and other polyols, amino acids, and organic and inorganic salts. In some embodiments, the magnesium-containing oxytocin peptide formulation or composition further comprises citrate, succinate, or pyrophosphate.

[0073] To further enhance mucosal delivery of the oxytocin peptide, enzyme inhibitors, particularly protease inhibitors, may further be included in the formulation. Protease inhibitors may include, but are not limited to, antipain, alphamenine A and B, benzamidine HCl, AEBSF, CA-074, calpain inhibitor I and II, calpeptin, pepstatin A, actinonin, amastatin, bestatin, boroleucine, captopril, chloroacetyl-HOLeu-Ala-Gly-NH2, DAPT, diprotin A and B, ebelactone A and B, foroxymithine, leupeptin, phosphoramidon, aprotinin, puromycin, BBI, soybean trypsin inhibitor, phenylmethylsulfonyl fluoride, E-64, chymostatin, 1,10-phenanthroline, EDTA, and EGTA. Other enzyme inhibitors, such as bacitracin, may also be included in the formulation.

[0074] Absorption enhancers may be included in the formulations to enhance delivery and / or absorption of the oxytocin peptide and magnesium salt into or across mucosal surfaces. These enhancers may increase the release or solubility (e.g., from the formulation delivery vehicle), diffusion rate, permeation capacity and timing, uptake, residence time, stability, effective half-life, peak or sustained concentration levels, clearance, and other desirable mucosal delivery properties (e.g., as measured at the delivery site) of the composition. Thus, enhanced mucosal delivery can occur by any of a variety of mechanisms, such as increasing the diffusion, transport, persistence, or stability of the oxytocin peptide, increasing membrane fluidity, modulating the availability or action of calcium and other ions that control intracellular or paracellular permeation, solubilizing mucosal components (e.g., lipids), altering non-protein and protein sulfhydryl levels in mucosal tissues, increasing water flux across mucosal surfaces, modulating epithelial junctional physiology, decreasing the viscosity of the mucus overlying the mucosal epithelium, decreasing the rate of mucociliary clearance, and other mechanisms.

[0075] Compounds that enhance mucosal absorption may include, but are not limited to, surfactants, bile salts, dihydrofusidates, bioadhesives / mucoadhesives, phospholipid additives, mixed micelles, liposomes or carriers, alcohols, enamines, cationic polymers, NO donor compounds, long-chain amphiphilic molecules, small molecule hydrophobic permeation enhancers; sodium or salicylic acid derivatives, glycerol esters of acetoacetic acid, cyclodextrins or beta-cyclodextrin derivatives, medium-chain fatty acids, chelating agents, amino acids or salts thereof, N-acetyl amino acids or salts thereof, mucolytic agents, enzymes specifically targeted to selected membrane components, inhibitors of fatty acid synthesis, and inhibitors of cholesterol synthesis.

[0076] All of the peptides described and / or contemplated herein can be prepared by chemical synthesis using automated or manual solid-phase synthesis techniques that are widely known in the art. The peptides can also be prepared using recombinant molecular methods known in the art.

[0077] (Delivery system) The magnesium-containing oxytocin peptide formulation or composition may be adapted for craniofacial mucosal administration (e.g., nasal, buccal, sublingual, or ocular administration). In some embodiments, the composition may further comprise a device for mucosal delivery. In some embodiments, the composition is adapted for buccal and / or sublingual mucosal delivery, and the composition may further comprise a device for buccal and / or sublingual mucosal administration (e.g., a unit-dose container, a pump spray, a dropper, a squeeze bottle, a preservative-free airless spray, a nebulizer, a dose inhaler, and a pressurized dose inhaler). In some embodiments, the composition is adapted for ocular delivery, and the composition may further comprise a device for conjunctival administration (e.g., a dropper or a squeeze bottle). In some embodiments, the composition is adapted for intranasal administration, and the composition may further comprise a device for intranasal administration (e.g., a dropper, a pump spray, a squeeze bottle, a preservative-free airless spray, or a nasal pump device, e.g., a nasal pump device comprising a reservoir bottle attached to an aerosolizer).

[0078] Intranasal drug delivery has been a topic of research and development for many years, but it is only within the last decade that carrier systems have been devised to effectively deliver substances (Sayani and Chien, Critical Reviews in Therapeutic Drug Carrier Systems 1996, 13:85-184). Intranasal delivery has several advantageous features, including relatively high bioavailability, rapid absorption kinetics, and avoidance of the first-pass effect in the liver. In some embodiments, intranasal administration can deliver oxytocin peptides to the nasal cavity, while in other embodiments, intranasal administration can enable targeted delivery to the cranial nerves of the nose and / or brain. Without wishing to be bound by any particular theory, intranasal administration of oxytocin peptides can target either the olfactory nervous system or the trigeminal nervous system, or both. Oxytocin peptides can be delivered intranasally in any applicable form, including, but not limited to, a liquid formulation, a solid formulation (e.g., a dry powder formulation), a gel formulation, or an emulsion formulation.

[0079] In embodiments in which the combination of oxytocin and a magnesium salt is administered intranasally, the composition may be prepared as a liquid aerosol formulation combined with a dispersing agent and / or a physiologically acceptable diluent. Alternatively, dry powder aerosol formulations are contemplated, which may include the subject compound in finely divided solid form and a dispersing agent that allows for rapid dispersion of the dry powder particles. In both liquid and dry powder aerosol formulations, the formulation is aerosolized into small liquid or solid particles to ensure that the aerosolized dose reaches the mucous membranes of the nasal passages or the lungs. The term "aerosol particles" is used herein to describe suitable liquid or solid particles with a particle diameter sufficiently small for distribution to the targeted mucous membranes or alveolar membranes in the nose (in the range of about 10 microns) or lungs (in the range of about 2-5 microns). Other considerations include the structure of the delivery device, additional components in the formulation, and particle characteristics. These aspects of nasal or pulmonary drug administration are well known in the art, and manipulation of the formulation, aerosolization means, and delivery device structure are within the level of ordinary skill in the art.

[0080] In some embodiments, a magnesium-containing oxytocin peptide formulation or composition is provided, comprising an oxytocin peptide and a magnesium salt, wherein the oxytocin peptide and the magnesium salt are present in amounts that provide synergistic analgesia when used to treat pain, and the formulation or composition further comprises a device for intranasal delivery. The device may be any device suitable for intranasal administration of a magnesium-containing oxytocin peptide formulation. In some embodiments, the device is suitable for delivering the oxytocin peptide and the magnesium salt to a specific region within the nasal cavity. In some embodiments, the device is suitable for delivering the oxytocin peptide and the magnesium salt to the lower two-thirds of the nasal cavity. In some embodiments, the device is suitable for delivering the oxytocin peptide and the magnesium salt to the upper one-third of the nasal cavity. In some embodiments, the device is suitable for delivering the oxytocin peptide to the entire nasal passage.

[0081] In some embodiments, the device for intranasal delivery is a nasal pump device. In some embodiments, the nasal pump device includes a reservoir bottle attached to a pump actuator. In some embodiments, the pump actuator metering delivers a specific volume (e.g., about 50 to about 150 μL, preferably about 50 μL or about 100 μL) with a specific droplet size distribution. In some embodiments, the nasal pump device includes a reservoir bottle attached to an aerosolizer, such as an Equadel pump sold by Aptar Pharma. In some embodiments, the device for nasal administration functions regardless of the pressure applied to the pump once a threshold is reached. For administration in larger mammals, the nasal pump device may include a reservoir bottle attached to a pump actuator metering delivers a larger volume (e.g., about 100 μL to about 600 μL or more).

[0082] In some embodiments, the device for intranasal delivery is designed to deliver multiple doses of a drug formulation. For example, a nasal pump device may include a reservoir bottle attached to a pump actuator, where the reservoir bottle holds multiple doses of a liquid formulation, and the pump actuator metering delivers a specific volume of the liquid formulation held in the reservoir bottle. In some embodiments, the pump actuator metering delivers approximately 50 μL of the liquid formulation per spray. The nasal pump device may include a filter to prevent backflow to reduce the ingress of contaminants (e.g., bacteria) into the reservoir bottle. In some embodiments, the nasal pump device includes a metal-free flow path (e.g., a plastic flow path) for delivering the liquid formulation. In some embodiments, the pump device uses a plastic material that is stable to gamma radiation (used to sterilize nasal devices). In some embodiments, the device for intranasal delivery includes a multi-dose pump with a microbial filter and an automatic blocking mechanism on the pump actuator, such as the spray device described in U.S. Pat. No. 5,988,449.

[0083] In some embodiments, the device for intranasal delivery is a breath-actuated nasal delivery device (e.g., the device described in U.S. Patent Nos. 7,784,460 and 7,854,227). Such devices can improve delivery to deep target sites within the nasal cavity. In some embodiments, a standard metered-dose spray device is incorporated into a housing, allowing the patient to breathe into the mouthpiece to activate the device. In some embodiments, the device comprises a conical, sealed nosepiece and mouthpiece incorporating a conventional mechanical spray pump (e.g., the Equadel pump sold by Aptar Pharma), a chargeable spring, and a breath-activated mechanism. The system can be used for single-dose or multiple-dose delivery. An example of such a liquid delivery device is the OptiMist™ device sold by OptiNose. In use, the nosepiece of the device is inserted into the nostril and the patient exhales into the mouthpiece. This closes the soft palate, putting pressure on the nostrils and opening a passageway behind the nasal septum that allows air to flow through and out the other nostril (two-way flow). The device is activated by exhalation, so small particles cannot enter the lungs. Modifying the flow rate and particle size allows for targeting of specific nasal areas.

[0084] In some embodiments, the device for intranasal delivery is a unit dose metered spray device suitable for single administration of the magnesium-containing oxytocin peptide formulation or composition, hi some embodiments, the device for intranasal delivery is a multi-dose metered spray pump device suitable for repeated administration of the oxytocin peptide.

[0085] Droplet size, plume volume, and flow rate can be modified to target specific nasal regions. Liquid sprays can provide droplet sizes between 5 and 50 microns to target the olfactory epithelium and / or respiratory epithelium. Larger droplets primarily land in the nasopharynx and are swallowed, while smaller droplets target lung tissue. The mass median equivalent aerodynamic diameter (MMAD) is used to determine droplet size. The pH of nasal sprays is optimized to deliver charged peptides in a nearly ionized state. The nose typically tolerates solutions with a pH of approximately 3 to 8. The nasal mucosa can typically absorb a volume of approximately 100 μL before saturation occurs and the liquid begins to drip out of the nose. Therefore, plume volumes can be up to (and including) 100 μL. For use in large mammals, plume volumes can be up to (and including) 150 μL or greater (e.g., 600 μL or greater). For use in infants and children, or for veterinary use in small animals (e.g., rodents, cats), smaller plume volumes (5-50 μL) can be used.

[0086] In some embodiments, the device for intranasal delivery is ergonomically designed to facilitate patient compliance (e.g., a pump device with a side-actuated trigger mechanism). In some embodiments, the device for intranasal delivery comprises a metered spray pump that operates as a closed system, preventing air from entering the pump device and therefore contamination with airborne microorganisms. In some embodiments, the device for intranasal delivery comprises a metered spray pump that operates with a filter. Passing air is drawn through a filter assembled within the pump, thereby keeping airborne microorganisms out of the pump device. In some embodiments, the intranasal delivery device comprising a nasal pump device may further comprise a microelectronic device that may facilitate data transmission and treatment monitoring.

[0087] In some embodiments, a magnesium-containing oxytocin peptide formulation or composition comprises an oxytocin peptide and a magnesium salt, wherein the oxytocin peptide and magnesium salt are contained in any one of the devices for intranasal delivery described herein, and the concentrations of the oxytocin peptide and magnesium salt are within any of the concentration ranges described herein, as if each and every combination of device and concentration were described individually.

[0088] (method) In one aspect, the present invention provides a method for treating pain, comprising administering an effective dose of an oxytocin peptide and a magnesium salt to a subject in need of pain treatment, wherein the co-administration of the oxytocin peptide and the magnesium salt results in synergistic analgesia. In some embodiments, the oxytocin peptide and the magnesium salt are administered at doses that result in an overall analgesic or analgesic effect that exceeds the sum of the analgesic or analgesic effects of equivalent doses of the oxytocin peptide and the magnesium salt administered separately. In some embodiments, the co-administration of the oxytocin peptide and the magnesium salt results in a reduction in the intensity or sensitivity of pain experienced by the subject to painful stimuli (allodynia and / or hyperalgesia) that exceeds the sum of the reductions in pain intensity or sensitivity to painful stimuli (allodynia and / or hyperalgesia) that are achieved by equivalent doses of the oxytocin peptide and the magnesium salt administered separately. In some embodiments, the co-administration of the oxytocin peptide and the magnesium salt results in a reduction in the frequency of pain experienced by the subject that exceeds the sum of the reductions in pain frequency that are achieved by equivalent doses of the oxytocin peptide and the magnesium salt administered separately. In some embodiments, co-administration of an oxytocin peptide with a magnesium salt results in a more rapid onset of analgesia or analgesia effect than an equivalent dose of any analgesic agent administered individually, hi some embodiments, co-administration of an oxytocin peptide with a magnesium salt results in a more long-lasting analgesia or analgesia effect than an equivalent dose of any analgesic agent administered individually.

[0089] The oxytocin peptide and the magnesium salt may be administered together or sequentially. In some embodiments, the oxytocin peptide is administered simultaneously with the magnesium salt in the same unit dose. In some embodiments, the oxytocin peptide is administered simultaneously with the magnesium salt but in separate unit doses or formulations. In some embodiments, the oxytocin peptide and the magnesium salt are administered sequentially. In some embodiments, the magnesium salt is administered to the subject in a first dose, and then the oxytocin peptide is administered to the subject in a second dose. In some of these embodiments, the oxytocin peptide is administered about 10 minutes to about 2 hours after administration of the magnesium salt. In some of these embodiments, the oxytocin peptide is administered about 10 minutes to about 2 hours, about 10 minutes to about 1 hour, about 10 minutes to about 30 minutes, about 20 minutes to about 2 hours, about 20 minutes to about 1 hour, about 30 minutes to about 2 hours, or about 30 minutes to about 1 hour after administration of the magnesium salt. In some of these embodiments, the oxytocin peptide is administered about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 90 minutes, or about 120 minutes after administration of the magnesium salt. In some of these embodiments, the oxytocin peptide is administered about 10 minutes, about 15 minutes, about 20 minutes, or about 30 minutes after administration of the magnesium salt. In one embodiment, the oxytocin peptide is administered to the subject first, and then the magnesium salt is administered to the subject. In some embodiments, the subject is a human.

[0090] The oxytocin peptide and the magnesium salt may be administered to a subject in need thereof via the same route or via different routes. In some embodiments, the oxytocin peptide is administered via craniofacial mucosal administration (e.g., nasal, buccal, sublingual, or ocular administration). In one embodiment, both the oxytocin peptide and the magnesium salt are administered intranasally in the same formulation. In one embodiment, the oxytocin peptide is administered via craniofacial mucosal administration, and the magnesium salt is administered systemically, for example, intravenously, intramuscularly, orally, subcutaneously, or intrathecally.

[0091] In some embodiments, the oxytocin peptide is administered via intranasal administration. In some embodiments, the oxytocin peptide and magnesium salt are administered via intranasal administration. The oxytocin peptide and / or magnesium salt can be administered to the mucosal tissue in the nasal cavity using a suitable device for intranasal delivery (e.g., a nasal delivery device described herein). Suitable areas in the nasal cavity include, but are not limited to, the lower two-thirds or upper one-third of the nasal cavity, or the entire nasal cavity. In some embodiments, the oxytocin peptide and / or magnesium salt is administered to the upper one-third of the nasal cavity. In some embodiments, the oxytocin peptide and / or magnesium salt is administered to the lower two-thirds of the nasal cavity. In some embodiments, the oxytocin peptide and / or magnesium salt is specifically administered to reach both the lower two-thirds and the upper one-third of the nasal cavity. In some embodiments, a method for treating pain is provided, comprising administering an effective dose of an oxytocin peptide and a magnesium salt intranasally to a subject in need of pain treatment, wherein the co-administration of the oxytocin peptide and the magnesium salt results in synergistic analgesia.

[0092] In some embodiments, the oxytocin peptide is human oxytocin consisting of Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly (SEQ ID NO: 1). In some embodiments, the effective dose of the oxytocin peptide is about 0.5 μg to about 2000 μg. In some embodiments, the effective dose of the oxytocin peptide is about 0.5 μg to about 1000 μg, about 1 μg to about 1000 μg, or about 1 μg to about 2000 μg. In some embodiments, an effective dose of oxytocin peptide is about 4 μg to about 1000 μg, about 8 μg to about 1000 μg, about 8 μg to about 800 μg, about 8 μg to about 500 μg, about 8 μg to about 400 μg, about 8 μg to about 300 μg, about 8 μg to about 200 μg, about 8 μg to about 100 μg, about 8 μg to about 80 μg, about 8 μg to about 50 μg, about 10 μg to about 1000 μg, about 10 μg to about 500 μg, about 10 μg to about 200 μg, about 10 μg to about 100 μg, about 16 μg to about 1000 μg, about 16 μg to about 800 μg, about 16 μg to about 500 μg, or about 16 μg to about 400 μg. g, about 16μg to about 200μg, about 16μg to about 160μg, about 16μg to about 120μg, about 16μg to about 80μg, about 20μg to about 100 0μg, about 20μg to about 800μg, about 20μg to about 500μg, about 20μg to about 200μg, about 20μg to about 100μg, about 30μg to about 1 000 μg, about 30 μg to about 500 μg, about 30 μg to about 300 μg, about 30 μg to about 120 μg, about 30 μg to about 90 μg, about 50 μg to about 1000 μg, about 50 μg to about 500 μg, about 50 μg to about 250 μg, about 50 μg to about 100 μg, or about 50 μg to about 80 μg. In some embodiments, the effective dose of oxytocin peptide is about 8 μg, about 16 μg, about 32 μg, about 48 μg, about 64 μg, about 80 μg, about 96 μg, about 128 μg, about 256 μg, about 10 μg, about 20 μg, about 30 μg, about 40 μg, about 50 μg, about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg, about 120 μg, about 150 μg, about 200 μg, about 400 μg, about 600 μg, about 800 μg, or about 100 μg. In preferred embodiments, the effective dose of oxytocin peptide is about 8 μg to about 120 μg, about 15 μg to about 120 μg, about 30 μg to about 120 μg, or about 66 μg.

[0093] In some embodiments, the effective dose of oxytocin peptide is about 0.25 IU to about 1000 IU. In some embodiments, the effective dose of oxytocin peptide is about 0.25 IU to about 500 IU, about 0.5 IU to about 500 IU, or about 0.5 IU to about 1000 IU. In some embodiments, an effective dose of oxytocin peptide is about 2 IU to about 500 IU, about 4 IU to about 500 IU, about 4 IU to about 400 IU, about 4 IU to about 250 IU, about 4 IU to about 200 IU, about 4 IU to about 150 IU, about 4 IU to about 100 IU, about 4 IU to about 50 IU, about 4 IU to about 40 IU, about 4 IU to about 25 IU, about 5 IU to about 500 IU, about 5 IU to about 250 IU, about 5 IU to about 100 IU, about 5 IU to about 50 IU, about 8 IU to about 500 IU, about 8 IU to about 400 IU, about 8 IU to about 250 IU, about 8 IU to about 200 IU , about 8 IU to about 100 IU, about 8 IU to about 80 IU, about 8 IU to about 60 IU, about 8 IU to about 40 IU, about 10 IU to about 500 IU, about 10 IU to about 400 IU, about 10 IU to about 250 IU, about 10 IU to about 100 IU, about 10 IU to about 50 IU, about 15 IU to about 500 IU, about 15 IU to about 250 IU, about 15 IU to about 150 IU, about 15 IU to about 60 IU, about 15 IU to about 45 IU, about 25 IU to about 500 IU, about 25 IU to about 250 IU, about 25 IU to about 125 IU, about 25 IU to about 50 IU, or about 25 IU to about 40 IU. In some embodiments, an effective dose of oxytocin peptide is about 4 IU, about 8 IU, about 16 IU, about 24 IU, about 32 IU, about 40 IU, about 48 IU, about 64 IU, about 128 IU, about 5 IU, about 10 IU, about 15 IU, about 20 IU, about 25 IU, about 30 IU, about 35 IU, about 40 IU, about 45 IU, about 50 IU, about 60 IU, about 75 IU, about 100 IU, about 200 IU, about 300 IU, about 400 IU, or about 50 IU. In preferred embodiments, an effective dose of oxytocin peptide is about 4 IU to about 60 IU, about 7.5 IU to about 60 IU, about 15 IU to about 60 IU, or about 30 IU.

[0094] In one embodiment, the dose or amount of oxytocin in the combination is effective to provide clinically measurable improvement of the symptoms of pain disorder.As described in the following examples, the combination of oxytocin and magnesium salt provides a synergistic effect of improving pain disorder.In some embodiments, oxytocin is administered at a sub-therapeutic dose relative to the dose of oxytocin administered as a single agent.The dose of oxytocin as a single agent depends in part on the route of administration.Therefore, the dose of oxytocin in the combination therapy described herein also depends in part on the route of administration.

[0095] The optimal dose of magnesium salt may depend on other factors such as the specific pain type, the type of synergistic effect desired, and the route of administration. The optimal dose depends on the total amount of magnesium salt administered, the amount of magnesium in the magnesium salt administered, the amount of magnesium ions (Mg 2+ ) or the concentration of magnesium ions in the administered formulation. In some embodiments, an effective dose of magnesium salt administered provides about 50 μg to about 68 mg of magnesium. In some embodiments, an effective dose of magnesium salt administered provides about 50 μg to about 34 mg or about 1 mg to about 3 mg of magnesium. In some embodiments, an effective dose of magnesium salt administered provides about 50 μg to about 68 mg of magnesium ions (Mg 2+ In some embodiments, the effective dose of magnesium salt administered is about 50 μg to about 34 mg or about 1 mg to about 3 mg of magnesium ion (Mg 2+ In some embodiments, the effective dose of magnesium salt administered is about 1.3 mg or about 2.6 mg of magnesium or Mg 2+ In some embodiments, the effective dose of magnesium salt administered is about 1.2 mg or about 2.4 mg of magnesium or Mg 2+In some embodiments, the effective dose of magnesium salt administered is about 50 μg to about 17 mg, about 50 μg to about 8 mg, about 50 μg to about 4 mg, about 50 μg to about 2 mg, about 50 μg to about 1 mg, about 50 μg to about 500 μg, about 100 μg to about 68 mg, about 100 μg to about 34 mg, about 100 μg to about 17 mg, about 100 μg to about 8 mg, about 100 μg to about 1 mg. g~about 4mg, about 100μg~about 2mg, about 100μg~about 1mg, about 100μg~about 500μg, about 200μg~about 68mg, about 200μg~about 34mg, about 200μg~about 17mg, about 200μg to about 8mg, about 200μg to about 4mg, about 200μg to about 2mg, about 200μg to about 1mg, about 200μg to about 500μg, about 500μg to about 68mg , about 500μg to about 34mg, about 500μg to about 17mg, about 500μg to about 8mg, about 500μg to about 5mg, about 500μg to about 4mg, about 500μg to about 3mg, about 500 μg~about 2mg, about 500μg~about 1mg, about 1mg~about 68mg, about 1mg~about 34mg, about 1mg~about 17mg, about 1mg~about 8mg, about 1mg~about 6mg, about 1mg~about 5 mg, about 1 mg to about 4 mg, about 1 mg to about 3 mg, about 1 mg to about 2 mg, about 1.5 mg to about 8 mg, about 1.5 mg to about 6 mg, about 1.5 mg to about 5 mg, about 1.5 mg to about 4 mg, about 1.5 mg to about 3 mg, about 1.5 mg to about 2 mg, about 1.3 mg to about 2.6 mg, or about 1.2 mg to about 2.4 mg of magnesium or magnesium ions (Mg 2+ In some embodiments, the magnesium salt is about 50 μg to about 68 mg, about 50 μg to about 34 mg, or about 1 mg to about 3 mg of magnesium or Mg 2+ In some embodiments, the magnesium salt is magnesium citrate and / or magnesium chloride administered in an amount that provides about 50 μg to about 68 mg, about 50 μg to about 34 mg, or about 1 mg to about 3 mg of magnesium or Mg. 2+ The present invention includes magnesium citrate and / or magnesium chloride administered in an amount that provides:

[0096] In some embodiments, the administered magnesium salt comprises magnesium chloride, and an effective dose of magnesium salt is about 0.48 mg to about 600 mg of magnesium chloride hexahydrate (MgCl 6H O, MW 203.3). In some embodiments, the effective dose of magnesium chloride hexahydrate is about 0.48 mg to about 300 mg, about 0.5 mg to about 150 mg, about 0.5 mg to about 75 mg, about 5 mg to about 150 mg, about 5 mg to about 75 mg, about 5 mg to about 50 mg, about 10 mg to about 600 mg, about 10 mg to about 300 mg, about 10 mg to about 150 mg, about 10 mg to about 75 mg, about 10 mg to about 50 mg, about 10 mg to about 30 mg, or about 12 mg to about 24 mg. In some preferred embodiments, the effective dose of magnesium chloride hexahydrate is about 6 mg, about 12 mg, about 18 mg, about 24 mg, or about 30 mg. In some embodiments, an effective dose of magnesium citrate is about 0.48 mg to about 12 mg, about 0.5 mg to about 10 mg, about 0.5 mg to about 8 mg, about 0.5 mg to about 5 mg, about 0.5 mg to about 2.5 mg, about 0.5 mg to about 1 mg, about 1 mg to about 10 mg, about 1 mg to about 8 mg, about 1 mg to about 5 mg, about 1 mg to about 2 mg, about 2 mg to about 10 mg, about 2 mg to about 8 mg, about 2 mg to about 6 mg, about 2 mg to about 4 mg, about 3 mg to about 10 mg, about 4 mg to about 10 mg, about 4 mg to about 8 mg, about 4 mg to about 6 mg, about 5 mg to about 10 mg, about 5 mg to about 8 mg, about 5 mg to about 7 mg, about 5 mg to about 6 mg, about 6 mg to about 10 mg, about 6 mg to about 8 mg, or about 6 mg to about 7 mg.

[0097] In some embodiments, the magnesium salt administered is magnesium citrate, and an effective dose of magnesium salt is about 0.48 mg to about 600 mg of magnesium citrate. In some embodiments, an effective dose of magnesium citrate (e.g., anhydrous dibasic magnesium citrate, molecular weight: 214.4) is about 0.48 mg to about 300 mg, about 0.5 mg to about 150 mg, about 0.5 mg to about 75 mg, about 5 mg to about 150 mg, about 5 mg to about 75 mg, about 5 mg to about 50 mg, about 10 mg to about 600 mg, about 10 mg to about 300 mg, about 10 mg to about 150 mg, about 10 mg to about 75 mg, about 10 mg to about 50 mg, about 10 mg to about 30 mg, or about 12 mg to about 24 mg. In some preferred embodiments, the effective dose of magnesium citrate (eg, anhydrous dibasic magnesium citrate, molecular weight: 214.4) is about 6 mg, about 12 mg, about 18 mg, about 24 mg, or about 30 mg. In some embodiments, an effective dose of magnesium citrate is about 0.48 mg to about 12 mg, about 0.5 mg to about 10 mg, about 0.5 mg to about 8 mg, about 0.5 mg to about 5 mg, about 0.5 mg to about 2.5 mg, about 0.5 mg to about 1 mg, about 1 mg to about 10 mg, about 1 mg to about 8 mg, about 1 mg to about 5 mg, about 1 mg to about 2 mg, about 2 mg to about 10 mg, about 2 mg to about 8 mg, about 2 mg to about 6 mg, about 2 mg to about 4 mg, about 3 mg to about 10 mg, about 4 mg to about 10 mg, about 4 mg to about 8 mg, about 4 mg to about 6 mg, about 5 mg to about 10 mg, about 5 mg to about 8 mg, about 5 mg to about 7 mg, about 5 mg to about 6 mg, about 6 mg to about 10 mg, about 6 mg to about 8 mg, or about 6 mg to about 7 mg. When other magnesium salts are used in place of magnesium citrate, an effective dose of the magnesium salt provides an amount of magnesium ions equivalent to the amount of magnesium citrate salt.

[0098] It is intended and understood that each and every dosage amount of the magnesium salt described herein can be combined with each and every dosage amount of the oxytocin peptide described herein as if each and every combination were individually stated. For example, in some embodiments, an effective dose of oxytocin peptide is about 0.5 μg to about 2000 μg, and an effective dose of magnesium salt administered provides about 50 μg to about 68 mg of magnesium. In some embodiments, an effective dose of oxytocin peptide is about 15 μg to about 120 μg (e.g., about 60 μg or about 66 μg), and an effective dose of magnesium salt administered is about 10 mg to about 30 mg (e.g., about 12 mg or about 24 mg) of magnesium citrate.

[0099] In some embodiments, methods are provided for treating pain, comprising administering (e.g., by intranasal administration) to a subject in need thereof effective doses of an oxytocin peptide and a magnesium salt, wherein the weight ratio of the administered dose of oxytocin peptide to the administered dose of magnesium or magnesium ions is about 1:1 to about 1:1000, preferably about 1:2 to about 1:200, more preferably about 1:20, about 1:30, about 1:35, about 1:40, about 1:45, about 1:50, about 1:60, or any of the OT / Mg(w) ratios described herein for magnesium-containing oxytocin peptide formulations or compositions. In some embodiments, methods are provided for treating pain, comprising administering (e.g., by intranasal administration) to a subject in need thereof an effective dose of an oxytocin peptide and a magnesium salt, wherein the molar ratio of the administered dose of oxytocin peptide to the administered dose of magnesium or magnesium ions is about 1:40 to about 1:40,000, preferably about 1:80 to about 1:8,000, more preferably about 1:500, about 1:800, about 1:1,000, about 1:1,200, about 1:1,400, about 1:1,600, about 1:1,800, about 1:2,000, about 1:2,400, about 1:3,000, or any of the OT / Mg(m) ratios described herein for magnesium-containing oxytocin peptide formulations or compositions. In some of these embodiments, the oxytocin peptide is human oxytocin consisting of Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly (SEQ ID NO: 1). In some of these embodiments, the magnesium salt is magnesium citrate. In some of these embodiments, the pain is a migraine headache.

[0100] In one embodiment, a method for treating pain is provided, comprising administering intranasally to a subject in need thereof about 0.5 μg to about 2000 μg (e.g., about 8 μg to about 300 μg, about 15 μg to about 120 μg, or about 66 μg) of an oxytocin peptide and about 50 μg to about 68 mg, about 50 μg to about 34 mg, about 1 mg to about 3 mg, about 1.3 mg, or about 2.6 mg of magnesium. In one embodiment, the method comprises administering intranasally to a subject in need thereof an effective dose of a magnesium-containing oxytocin peptide formulation or composition described herein. In one embodiment, the method comprises administering to a subject in need thereof an effective dose of a magnesium-containing oxytocin peptide formulation or composition containing about 0.01 mg / mL to about 16 mg / mL (e.g., about 0.1 mg / mL and about 16 mg / mL) of oxytocin and about 1 mg / mL to about 30 mg / mL of magnesium or magnesium ions. In one embodiment, the method comprises administering to a subject in need thereof an effective dose of a magnesium-containing oxytocin peptide formulation containing about 0.01 mg / mL to about 16 mg / mL (e.g., about 0.1 mg / mL to about 16 mg / mL or about 0.15 mg / mL to about 1.5 mg / mL) of oxytocin and about 1% (by weight) to about 25% (by weight) (e.g., about 1% to about 15% or about 10% to about 14%) of magnesium citrate. In one embodiment, the method includes administering into the nasal cavity of a subject in need thereof an effective dose of a magnesium-containing oxytocin peptide formulation comprising about 5 IU / mL to about 8000 IU / mL (e.g., about 50 IU / mL to about 8000 IU / mL or about 75 IU / mL to about 750 IU / mL) of oxytocin and about 1% (by weight) to about 25% (by weight) (e.g., about 1% to about 15%, about 10% to about 14%, or about 12%) of magnesium citrate.In one embodiment, the method includes administering intranasally to a subject in need thereof an effective dose of a magnesium-containing oxytocin peptide formulation comprising about 0.01 mg / mL to about 16 mg / mL (e.g., about 0.1 mg / mL and about 16 mg / mL, or about 0.15 mg / mL and about 1.5 mg / mL) of oxytocin and about 1% (by weight) to about 25% (by weight) (e.g., about 1% to about 15%, about 8% to about 12%, or about 10%) of magnesium chloride hexahydrate. In one embodiment, the method includes administering into the nasal cavity of a subject in need thereof an effective dose of a magnesium-containing oxytocin peptide formulation containing about 5 IU / mL to about 8000 IU / mL (e.g., about 50 IU / mL to about 8000 IU / mL or about 75 IU / mL to about 750 IU / mL) of oxytocin and about 1% (by weight) to about 25% (by weight) (e.g., about 1% to about 15%, about 8% to about 12%, or about 10%) of magnesium chloride hexahydrate.

[0101] In some embodiments, an effective dose of oxytocin peptide and magnesium salt comprises about 0.5 μg (or 0.25 IU) to about 2000 μg (or 1000 IU) of oxytocin peptide administered in an aqueous solution containing about 0.1% to about 2.8% (w / v) magnesium. In some embodiments, an effective dose of oxytocin peptide and magnesium salt comprises about 8 μg (or 4 IU) to about 1000 μg (or 500 IU) of oxytocin peptide administered in an aqueous solution containing about 0.11% to about 1.65% (w / v) magnesium. In some embodiments, an effective dose of oxytocin peptide and magnesium salt comprises about 15 μg (or 7.5 IU) to about 120 μg (or about 60 IU) (e.g., about 60 μg or 30 IU) of oxytocin peptide administered in an aqueous solution containing about 1.1% to about 1.6% (e.g., about 1.2% or about 1.35%) magnesium. In one embodiment, an effective dose of oxytocin peptide and magnesium salt comprises about 60 μg (or 30 IU) of oxytocin peptide administered in an aqueous solution containing about 1.2% or about 1.35% magnesium.

[0102] In some embodiments, an effective dose of oxytocin peptide and magnesium salt comprises about 0.5 μg to about 2000 μg of oxytocin peptide administered in an aqueous solution containing about 1% to about 25% magnesium citrate (by weight). In some embodiments, an effective dose of oxytocin peptide and magnesium salt comprises about 8 μg to about 1000 μg of oxytocin peptide administered in an aqueous solution containing about 1% to about 15% magnesium citrate (by weight). In some embodiments, an effective dose of oxytocin peptide and magnesium salt comprises about 15 μg to about 120 μg (e.g., about 66 μg) of oxytocin peptide administered in an aqueous solution containing about 10% to about 14% (e.g., about 12%) magnesium citrate. In one embodiment, an effective dose of oxytocin peptide and magnesium salt comprises about 66 μg of oxytocin peptide administered in an aqueous solution containing about 12% magnesium citrate.

[0103] The synergistic combination of oxytocin peptide and magnesium salt can be used to treat any pain treatable by oxytocin, such as orofacial and craniofacial pain (e.g., headache), neck pain (e.g., occipital neuralgia), or upper extremity pain. Thus, a method for treating pain is provided, comprising administering an effective dose of an oxytocin peptide and a magnesium salt to a subject in need of pain treatment, wherein the pain is orofacial and craniofacial pain, neck pain, or upper extremity pain, and the co-administration of the oxytocin peptide and the magnesium salt results in synergistic analgesia. In one embodiment, the method comprises administering an effective dose of an oxytocin peptide and a magnesium salt intranasally to a subject in need of pain treatment.

[0104] In some embodiments, the pain is somatic pain. In some embodiments, the pain is superficial somatic pain. In some embodiments, the pain is deep somatic pain. In some embodiments, the pain is musculoskeletal pain. In some embodiments, the pain is visceral pain. In some embodiments, the pain is neuropathic pain. In some embodiments, the pain is headache or craniofacial pain. In some embodiments, the pain is pain in a part of the body other than the head region and / or orofacial region. In some embodiments, the pain is chronic pain, such as the chronic pain described herein. In some embodiments, the pain is acute pain, such as the acute pain described herein. In some embodiments, the pain is a combination of one or more of the pains described herein. In some embodiments, the pain is sharp and aching pain associated with movement. In some embodiments, the pain is neuropathic pain caused by nerve injury, such as nerve injury associated with surgery.

[0105] In some embodiments, the pain is headache. In some embodiments, the pain is facial pain. In some embodiments, the pain is neck pain. In some embodiments, the pain is occipital neuralgia. In some embodiments, the pain is upper extremity pain. Examples of neck pain and upper extremity pain include, but are not limited to, nerve compression disorders (spinal stenosis), disc and vertebral diseases, diabetic neuropathy, carpal tunnel syndrome, arthritic diseases, post-traumatic injury, intervertebral disorders, and post-herpetic neuralgia. In some embodiments, the pain is exacerbated by a psychiatric disorder such as depression, anxiety, or stress. In some embodiments, the pain is induced or exacerbated by food (e.g., caffeine, chocolate, alcohol) or substance abuse (e.g., opiates).

[0106] Some aspects of the present invention include a method for treating trigeminal nerve-associated pain, comprising administering an effective dose of an oxytocin peptide and a magnesium salt to a subject in need of such treatment, wherein the simultaneous administration of the oxytocin peptide and the magnesium salt results in synergistic analgesia. In some embodiments, a method for treating trigeminal nerve-associated pain is provided, comprising administering (e.g., intranasally) an effective dose of a magnesium-containing oxytocin peptide formulation or composition described herein to a subject in need of such treatment. The trigeminal nerve-associated pain may be selected from the group consisting of chronic pain, acute pain, and procedural pain, as well as combinations thereof. In some instances, the chronic pain is selected from the group consisting of trigeminal neuralgia, atypical facial pain, painful numbness, postherpetic neuralgia, head and neck cancer, migraine, and temporomandibular joint pain (TMJ). In some instances, the procedural pain is pain resulting from a dental, medical, surgical, or cosmetic procedure. In still other examples, acute pain is pain resulting from lacerations, burns, fractures, injuries, headaches, abscessed teeth, dental disease, bacterial infections or sinus infections.Chronic pain, acute pain or procedural pain associated with the trigeminal nervous system occurs in many syndromes and diseases, including but not limited to trigeminal neuralgia, atypical facial pain, painful numbness, postherpetic neuralgia, head and neck cancer, migraine, other types of headache, TMJ, injuries to the face and / or head, dental injury or infection, general dental procedures, and facial surgery such as cosmetic plastic surgery.

[0107] Chronic pain in the face and head region can result from a variety of conditions, including, but not limited to, neuropathic pain, headache, TMJ, cancer and / or cancer treatment pain. These pain syndromes are often not effectively treated with current medications or invasive interventions, and new methods for localized pain relief in the face and head region are needed. Therefore, some embodiments of the present invention include a method for treating a subject for trigeminal nerve-related chronic pain by administering an effective dose of a magnesium-containing oxytocin peptide formulation or composition described herein, wherein the administration targets the trigeminal nervous system and provides analgesia primarily in the face, head, or neck region, particularly compared to analgesic effects in other body parts. The magnesium-containing oxytocin peptide formulation or composition can be administered to patients with neuropathic pain, including, but not limited to, trigeminal neuralgia, atypical facial neuralgia, and postherpetic neuralgia. The magnesium-containing oxytocin peptide formulation or composition can be administered to subjects with headaches, such as migraines or cluster headaches. The magnesium-containing oxytocin peptide formulation or composition may be administered to a subject with chronic pain resulting from head or face cancer or from previous treatment for head or face cancer.

[0108] In some embodiments, the present invention provides methods for treating a subject for trigeminal nerve-related pain resulting from a medical, dental, or cosmetic procedure, comprising administering an effective dose of a magnesium-containing oxytocin peptide formulation or composition described herein, wherein the administration targets the trigeminal nervous system and results in analgesia primarily in the facial or head region. The methods may include administering a magnesium-containing oxytocin peptide formulation or composition to a subject undergoing a procedure selected from the group consisting of medical, dental, and cosmetic procedures. These methods may include medical, dental, or cosmetic procedures selected from the group consisting of microdermabrasion, Botox injections, photodynamic therapy or other skin tumor ablation procedures, hair removal (including electrolysis, laser, waxing, etc.), general facial laser treatments (including pigment removal and vascular lesions), dermal and subcutaneous injectable fillers (including collagen, hyaluronic acid, methyl methacrylate, hydroxyapatite, etc.), chemical or laser facial peeling, photofacials, collagen contraction procedures (including radiofrequency, HIFU, high-intensity light, laser, etc.), dental procedures, tattooing, tattoo removal, piercing, and steroid injection scar and keloid treatment. Magnesium-containing oxytocin peptide formulations or compositions can be administered to patients undergoing a procedure, and the analgesic effect lasts for the duration of the procedure. Magnesium-containing oxytocin peptide formulations or compositions can be administered to patients undergoing a procedure, and the time required for the procedure and analgesia is more than 90 minutes. Administration of the magnesium-containing oxytocin peptide formulations or compositions described herein can result in immediate analgesia in a patient undergoing a procedure, and / or the analgesia persists for the entire duration of the procedure.

[0109] Some aspects of the present invention include methods for treating a subject for trigeminal nerve-related pain resulting from a medical, dental, or cosmetic procedure, comprising administering an effective dose of a magnesium-containing oxytocin peptide formulation or composition described herein, where the administration targets the trigeminal nervous system and results in localized analgesia in the face, head, or neck. The methods may include an effective dosage such that the localized analgesia persists for the duration of the procedure and continues into the post-operative period. These methods may include medical, dental or cosmetic procedures selected from the group consisting of periodontal surgery, dental reconstruction surgery, palate surgery, tooth extraction, root canal surgery, rhytidectomy, blepharoplasty, eyelash lift, rhinoplasty, cheek implants, chin implants, fat injection, lesion removal, excision biopsy, Mohs surgery, flap reconstruction, surgical orthodontics, ophthalmic surgery, oculoplastic surgery, hair transplant surgery, extensive laser resurfacing, laceration repair, nasal bone fracture repair, facial bone fracture repair, burn debridement and wound irrigation.Magnesium-containing oxytocin peptide preparations or compositions can be administered to the face or head area of ​​patients undergoing medical procedures before injection of vasoconstrictors.Magnesium-containing oxytocin peptide preparations or compositions can be administered to patients undergoing medical procedures, and the analgesia lasts beyond the time of the procedure and continues into the post-operative period. The magnesium-containing oxytocin peptide formulation or composition can be administered to a patient undergoing a medical procedure, and the analgesia lasts for several hours to several days after the procedure is completed.

[0110] In certain embodiments, the present invention provides a method for treating migraine, comprising administering (e.g., intranasally) an effective dose of an oxytocin peptide and a magnesium salt to a human or animal subject in need of migraine treatment, wherein the co-administration of the oxytocin peptide and the magnesium salt results in synergistic analgesia. In some embodiments, the oxytocin peptide and the magnesium salt are administered at a dose that results in an overall efficacy that exceeds the sum of the efficacy of equivalent doses of the oxytocin peptide and the magnesium salt administered separately. In some embodiments, the oxytocin peptide and the magnesium salt are administered at a dose that results in an overall analgesic or analgesic effect that exceeds the sum of the analgesic or analgesic effects of equivalent doses of the oxytocin peptide and the magnesium salt administered separately. In some embodiments, the co-administration of the oxytocin peptide and the magnesium salt results in a reduction in the intensity and / or pain sensitivity (allodynia and / or hyperalgesia) of the migraine experienced by the subject that exceeds the sum of the reductions in pain intensity or pain sensitivity (allodynia and / or hyperalgesia) caused by equivalent doses of the oxytocin peptide and the magnesium salt administered separately. In some embodiments, co-administration of an oxytocin peptide with a magnesium salt results in a reduction in the frequency of migraine attacks experienced by a subject that exceeds the combined reduction in migraine attack frequency achieved by equivalent doses of oxytocin peptide and magnesium salt administered separately. In some embodiments, co-administration of an oxytocin peptide with a magnesium salt results in a more rapid onset of analgesic or analgesic effect (e.g., reduction or relief of migraine headaches) than an equivalent dose of any analgesic administered separately. In some embodiments, co-administration of an oxytocin peptide with a magnesium salt results in a longer-lasting analgesic or analgesic effect (e.g., reduction or relief of migraine headaches) than an equivalent dose of any analgesic administered separately.

[0111] In one embodiment, a method for treating migraine is provided, comprising intranasally administering an effective dose of an oxytocin peptide and a magnesium salt to a subject (e.g., a human or animal patient) in need of migraine treatment, wherein co-administration of the oxytocin peptide and the magnesium salt results in synergistic analgesia. In some embodiments, the oxytocin peptide is human oxytocin consisting of Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly (SEQ ID NO: 1). In some embodiments, the effective dose of the oxytocin peptide is from about 0.5 μg (or 0.25 IU) to about 2000 μg (or 1000 IU), preferably from about 8 μg (or 4 IU) to about 1000 μg (or 500 IU), and more preferably from about 15 μg (or 7.5 IU) to about 120 μg (or 60 IU). In some embodiments, an effective dose of magnesium salt administered provides about 50 μg to about 68 mg of magnesium. In some embodiments, the magnesium salt is magnesium chloride and / or magnesium citrate administered in an amount providing about 50 μg to about 68 mg of magnesium. In some embodiments, an effective dose of magnesium salt is about 0.48 mg to about 600 mg of magnesium citrate. In some embodiments, an effective dose of magnesium salt is about 0.42 mg to about 540 mg of magnesium chloride hexahydrate. In some embodiments, an effective dose of oxytocin peptide and magnesium salt comprises about 15 μg (or 7.5 IU) to about 120 μg (or 60 IU) (e.g., about 60 μg or 30 IU) of oxytocin peptide administered in an aqueous solution containing about 1.1% to about 1.54% (e.g., about 1.2% or about 1.35%) (w / v) magnesium. In some embodiments, an effective dose of oxytocin peptide and magnesium salt comprises about 15 μg to about 120 μg (e.g., about 66 μg) oxytocin peptide administered in an aqueous solution containing about 10% to about 14% (e.g., about 12%) (w / v) magnesium citrate.In one embodiment, a method for treating migraine headaches includes administering intranasally to a subject in need thereof about 0.5 μg to about 2000 μg (e.g., about 15 μg to about 120 μg or about 66 μg) of an oxytocin peptide and about 50 μg to about 68 mg (e.g., about 50 μg to about 34 mg of magnesium or about 1 mg to about 3 mg) of magnesium salt. In one embodiment, a method for treating migraine headaches includes administering intranasally to a subject in need thereof about 0.25 IU to about 1000 IU (e.g., about 7.5 IU to about 60 IU or about 30 IU) of an oxytocin peptide and about 50 μg to about 68 mg (e.g., about 50 μg to about 34 mg of magnesium or about 1 mg to about 3 mg) of magnesium salt. In one embodiment, the method comprises administering intranasally to a subject in need thereof an effective dose of a magnesium-containing oxytocin peptide formulation or composition described herein (e.g., a magnesium-containing oxytocin peptide formulation or composition comprising about 0.01 mg / mL to about 16 mg / mL of oxytocin and about 1 mg / mL to about 30 mg / mL of magnesium or magnesium ions). In one embodiment, the method comprises administering intranasally to a subject in need thereof an effective dose of a magnesium-containing oxytocin peptide formulation comprising about 0.01 mg / mL to about 16 mg / mL (preferably, about 0.1 mg / mL to about 2 mg / mL, more preferably, about 0.15 mg / mL, about 1.5 mg / mL, or about 0.33 mg / mL) of oxytocin and about 1% (by weight) to about 25% (by weight) (e.g., about 10% to about 14%) magnesium citrate. In one embodiment, the method includes administering into the nasal cavity of a subject in need thereof an effective dose of a magnesium-containing oxytocin peptide formulation containing about 5 IU / mL to about 8000 IU / mL (preferably about 50 IU / mL to about 1000 IU / mL, more preferably about 75 IU / mL to about 750 IU / mL or about 150 IU / mL) of oxytocin and about 0.1% (by weight) to about 2.8% (by weight) (e.g., about 1.1% to about 1.54%) of magnesium.

[0112] Some aspects of the present invention include methods for treating cervical nerve-associated pain, comprising administering an effective dose of an oxytocin peptide and a magnesium salt to a subject in need of such treatment. In some embodiments, co-administration of an oxytocin peptide and a magnesium salt results in synergistic analgesia. In some embodiments, the method is for treating upper cervical nerve-associated pain. There are eight cervical nerves (C1-C8) on each side of the body. The upper cervical nerves (C1-C4) provide innervation and transmit pain information from the back of the head, neck, and upper shoulders. The lower cervical nerves (C5-C8) transmit pain information from the lower shoulders, arms, and hands, including the fingers. "Cervical nerve-associated pain," as used herein, unless otherwise specified, refers to pain arising in tissues innervated by cervical nerves and / or associated with injury or trauma to the cervical nerves. In some embodiments, the cervical nerve-associated pain is associated with the upper cervical nerves, such as the C1, C2, C3, and / or C4 nerves. "Upper cervical nerve-associated pain," as used herein, refers to pain arising in tissues innervated by one or more upper cervical nerves and / or associated with injury or trauma to one or more upper cervical nerves.

[0113] In some embodiments, a method for treating cervical nerve-associated pain is provided, comprising administering (e.g., by intranasal administration) an effective dose of a magnesium-containing oxytocin peptide formulation or composition described herein to a subject in need thereof. In some embodiments, the method comprises treating chronic or persistent pain in the neck, shoulder, and / or upper limb. In some embodiments, the method comprises treating cervical nerve-associated pain. In some embodiments, the method comprises treating upper cervical nerve-associated pain (e.g., neck pain). In some embodiments, the method comprises treating lower cervical nerve-associated pain (e.g., pain in the shoulder, forearm, or hand). In some embodiments, the method comprises treating occipital pain or neck pain. In some embodiments, the method comprises treating occipital neuralgia. In some embodiments, the method comprises treating shoulder pain. In some embodiments, the method comprises treating pain in the forearm or upper arm. In some embodiments, the effective dose of oxytocin peptide administered is about 50 to about 8000 IU, about 50 to about 2000 IU, about 50 to about 150 IU, or about 150 to about 2000 IU. In some embodiments, the effective dose is about 50 to about 150 IU, about 50 to about 100 IU, about 60 to about 90 IU, about 100 to about 150 IU, about 120 to about 150 IU, or about 75 to about 150 IU. In some embodiments, the effective dose is about 150 IU to about 2000 IU, about 150 IU to about 1000 IU, about 150 IU to about 500 IU, about 200 IU to about 2000 IU, about 200 IU to about 1000 IU, about 200 IU to about 500 IU, about 250 IU to about 2000 IU, about 250 IU to about 1000 IU, about 250 IU to about 500 IU, about 500 IU to about 2000 IU, or about 500 IU to about 1000 IU. In some embodiments, the effective dose is about 100 IU to about 1000 IU. In some embodiments, the effective dose of the magnesium salt administered is about 50 μg to about 34 mg or about 1 mg to about 3 mg of magnesium or magnesium ions (Mg 2+In some embodiments, the effective dose of magnesium salt administered is about 50 μg to about 1 mg, about 0.5 mg to about 5 mg, about 3 mg to about 15 mg, or about 5 mg to about 30 mg of magnesium or Mg 2+ In some embodiments, the effective dose of magnesium salt administered is about 1.2 mg or about 2.4 mg of magnesium or Mg 2+ Generally, higher doses of oxytocin peptide formulations are required to treat cervical nerve-associated pain than trigeminal nerve-associated pain; and higher doses of oxytocin peptide formulations are required to treat lower cervical nerve-associated pain than upper cervical nerve-associated pain.

[0114] (kit) Kits for carrying out any of the methods described herein are provided herein. Kits for use in the treatment and / or prevention of pain are provided. In some embodiments, the kits include an oxytocin peptide and a magnesium salt (wherein the oxytocin peptide and the magnesium salt are present in amounts that provide synergistic analgesia when used in the treatment of pain) and a device for craniofacial mucosal administration (e.g., intranasal administration) in suitable packaging. The kit may further include a protease inhibitor and / or at least one absorption enhancer. Other kits may further include instructions that provide information to a user and / or a healthcare provider for carrying out any of the methods described herein.

[0115] Also provided are kits comprising the magnesium-containing oxytocin peptide formulations described herein contained in a device for craniofacial mucosal administration (e.g., a device for intranasal administration such as a nasal pump device) and suitable packaging. The kits may further include instructions for administering the magnesium-containing oxytocin peptide formulation to a subject in need thereof.

[0116] The instructions for using a kit to practice the invention will generally describe how to use the contents of the kit to practice the method of the invention. The instructions provided with the kit of the invention will typically be written instructions on a label or package insert (e.g., a paper sheet included with the kit), although machine-readable instructions (e.g., instructions on a magnetic or optical storage disk) are also acceptable. [Example]

[0117] The present invention may be further understood by reference to the following examples, which are provided for purposes of illustration and are not intended to be limiting.

[0118] Example 1: Effects of magnesium chloride or magnesium lactate in a rat model of facial thermal pain sensation Heat from a flood lamp was focused on the pre-shaved rat cheek, and the intensity was varied to elicit a withdrawal response with a latency of 6.5 to 8.5 seconds. The intensity applied to achieve such a latency was recorded for each animal. Once a stable / acceptable baseline was obtained, the mean latency for each rat was calculated. After measuring baseline cheek withdrawal latencies for all rats, each rat received a single intranasal administration of either normal saline, 15% magnesium chloride aqueous solution, or 1% magnesium lactate aqueous solution according to the method developed by Frey (Thorne et al., Neuroscience., 127:481-496 (2004)). Briefly, rats (under urethane anesthesia) were placed in a dorsal recumbent position with a roll pad (2 x 2 gauze) inserted under the dorsal neck, and the head was extended toward the support surface. The upper surface of the neck was maintained horizontal throughout the administration procedure to maintain the drug solution in the nasal cavity and minimize drooling from the nasopharynx. A 6 μL drop of each drug solution was dispensed from the tip of a small pipette and administered to the rat's left nostril while the opposite nostril was blocked. Alternating doses were administered to each nostril every 2 minutes (thus essentially resulting in a 4-minute interval between doses to the same nostril). Four drops were administered to each nostril, for a total volume of 48 μL (8 drops of 6 μL each). Drug solutions were coded to maintain experimenter blindness to the substance delivered. Left cheek withdrawal latencies to radiant heat stimulation were then measured over the next 3 hours. Withdrawal latencies were measured before intranasal administration and 1, 2, and 3 hours after treatment.

[0119] Withdrawal latencies to thermal stimuli (noxious heat) were recorded as an index of thermal sensitivity. Prolonged latencies were considered indicative of analgesia / antinociception. Nasal application of saline transiently prolonged rats' response latencies by approximately 1.2 seconds, suggesting a mild analgesic effect that persisted until the 2-hour test time point, although the latencies at 2 hours were actually lower than baseline reactivity (Figure 1). Application of 1% magnesium lactate also produced a mild analgesic effect, prolonging response latencies by approximately 1.5 seconds. However, unlike saline application, latencies after magnesium lactate application remained substantially prolonged at both the 2-hour and 3-hour test time points. Application of 15% magnesium chloride solution produced a stronger analgesic effect 1 hour after testing than rats treated nasally with saline, and analgesia persisted at 2 and 3 hours after administration.

[0120] To the inventors' knowledge, this surprising result is the first finding that nasal application of a magnesium salt is analgesic.

[0121] Example 2: Dose-dependence of the analgesic effect of intranasally administered magnesium citrate in a rat model of facial thermal pain sensation One of four concentrations of dibasic magnesium citrate (1:1 Mg / citric acid) was applied to rats, and the effects of these applications on the response to noxious facial heat stimuli were evaluated as described above. Following the method described above, each rat received a single intranasal administration of 3, 6, 10, or 12% aqueous magnesium citrate solution (6 rats per group). The left cheek withdrawal latency to radiant heat stimuli was then measured over the following 300 minutes. The withdrawal latency was measured before intranasal administration and 15, 30, 45, 60, 120, 180, 240, and 300 minutes after treatment.

[0122] Magnesium citrate was prepared by adding USP anhydrous magnesium carbonate (MgCO, Acros Organics, 9.5 g) to a citric acid solution (22 g citric acid monohydrate in 80 ml dH2O) heated to 60°C and stirring until the mixture was completely clear. The mixture was then filtered. The magnesium citrate product was precipitated using absolute ethanol, washed, and dried on a hot plate at 60°C.

[0123] Nasal application of aqueous solutions of magnesium citrate produced a clear dose-dependent analgesic effect in rats, as indicated by prolonged withdrawal latencies in response to noxious cheek heating (Fig. 2). Thus, with positive findings for three of the three magnesium salts, these experiments provided evidence of principle that nasal application of salts providing magnesium ions in aqueous solution is analgesic.

[0124] Example 3: Dose-dependence of the analgesic effect of intranasally administered oxytocin in a rat model of facial thermal pain Oxytocin was administered in one of three doses in buffered saline to rats, and the effects of these doses on the response to noxious facial heat stimuli were evaluated as described above. Following the method described above, each rat received a single intranasal administration of an aqueous solution containing 1, 4, or 8 μg of oxytocin (6 rats per group). The left cheek withdrawal latency to radiant heat stimuli was then measured over the following 300 minutes. The withdrawal latency was measured before intranasal administration and 15, 30, 45, 60, 120, 180, 240, and 300 minutes after treatment.

[0125] Intranasal application of an aqueous solution of oxytocin produced a clear dose-dependent analgesic effect in rats, as indicated by the prolongation of the withdrawal latency to noxious cheek heating (Figure 3). Both 4 μg and 8 μg of oxytocin administered intranasally produced a significant prolongation of the withdrawal latency to noxious cheek heating. However, 1 μg of oxytocin administered intranasally was subtherapeutic and showed no prolongation of the withdrawal latency (in fact, a slight shortening). The dose-dependent analgesic effect of this intranasal oxytocin peptide is consistent with the analgesic effects we have previously reported for oxytocin.

[0126] Example 4: Analgesic effects of drug combination solutions with various ratios of magnesium salt and oxytocin Example 4A - Magnesium Citrate / Oxytocin Combination An aqueous solution containing one of three concentrations of magnesium citrate combined with one of three doses of oxytocin was administered intranasally to rats, and changes in withdrawal latency were measured as described above. Following the method described above, each rat received a single intranasal dose of 1, 4, or 8 μg of oxytocin in an aqueous solution containing 3, 6, or 12% magnesium citrate. The left cheek withdrawal latency to radiant heat stimulation was then measured over the following 300 minutes. Withdrawal latencies were measured before intranasal administration and 15, 30, 45, 60, 120, 180, 240, and 300 minutes after treatment.

[0127] A difference score was generated for each post-administration time point by comparing each withdrawal latency to the pre-administration (baseline) value. As a standard means of assessing combination effects, difference scores were also calculated for the effects of intranasal magnesium citrate alone (from Experiment 2 above) and intranasal oxytocin alone (from Experiment 3 above). The predicted additive effects of oxytocin dose + magnesium citrate concentration combinations were then calculated and compared with the measured difference scores measured by the actual administration of these combinations. If the measured combination effect exceeds the predicted additive effect, this, by definition, exemplifies pharmacological synergy. This synergy may be evidenced by an unexpected increase in latency beyond additive, either earlier than the expected onset of analgesia or longer than the expected duration of effect.

[0128] Nasal application of various doses of oxytocin in combination with various concentrations of magnesium citrate often produced surprising levels of analgesia, far exceeding those expected based on the effects of oxytocin or magnesium citrate alone. For doses of oxytocin (1 μg) that were ineffective or subtherapeutic alone, the addition of 3, 6, or 12% magnesium citrate produced substantial analgesia. For all post-administration time points, the increase in response latency above baseline observed after administration of 1 μg of oxytocin in 6% magnesium citrate exceeded the effects that would be predicted or expected by combining the effects of 1 μg of oxytocin and 6% magnesium citrate alone (Figures 4A and 4C). A similar supra-additive effect was observed 45 minutes after administration of 1 μg of oxytocin in 3 or 12% magnesium citrate (Figures 4B and 4D).

[0129] At least at some time points, a more-than-additive effect was observed even for a moderately analgesic dose of oxytocin (4 μg) when administered as a magnesium citrate formulation. For example, Figure 5 demonstrates that the analgesic effect observed 120 minutes after administration substantially exceeded that predicted by combining the effects of its two components. For a strongly analgesic dose of oxytocin (8 μg) in this model, intranasal application in magnesium citrate solution substantially increased the efficacy of that dose. At most time points, the analgesia observed after administration of 8 μg of oxytocin in 12% magnesium citrate solution exceeded that predicted by combining the individual effects of the two components (Figures 6A and 6D). Another important finding is that the combination not only exhibited a greater amplitude of effect (i.e., latency difference from baseline), but also a faster onset of effect and a longer duration of analgesia. Similar supra-additive effects were observed at several time points following intranasal application of 8 μg of oxytocin in 3 or 6% magnesium citrate. For example, Figures 6B and 6C demonstrate that the analgesic effect observed 15 minutes after administration substantially exceeded that predicted or expected by combining the effects of the two components.

[0130] Example 4B - Magnesium Sulfate / Oxytocin Combination An aqueous solution containing a combination of magnesium sulfate and oxytocin was administered intranasally to rats, and changes in withdrawal latency were measured as described above. Following the method described above, each rat received a single intranasal dose of 8 μg of oxytocin in an aqueous solution containing 20% ​​magnesium sulfate heptahydrate (MgSO4·7H2O, MW 246.5). Left cheek withdrawal latency to radiant heat stimulation was then measured over the following 300 minutes. Withdrawal latencies were measured before intranasal administration and at 15, 30, 45, 60, 120, 180, 240, and 300 minutes after treatment.

[0131] The increase in response latency above baseline observed after administration of 8 μg of oxytocin in 20% magnesium sulfate heptahydrate exceeded what would be predicted or expected by combining the effects of 8 μg of oxytocin alone and 20% magnesium sulfate heptahydrate alone. Figure 7 demonstrates that the analgesic effect observed 120 minutes after administration substantially exceeded what would be predicted or expected by combining the effects of its two components.

[0132] The results of these experiments clearly suggest that: 1) intranasal application of magnesium salts at various concentrations surprisingly produces analgesia; 2) as expected, intranasal application of oxytocin peptide is potently and dose-dependently analgesic; and 3) adding various concentrations of magnesium salts to subtherapeutic, moderately analgesic, and strongly analgesic doses of oxytocin surprisingly and unpredictably produces greater than additive (synergistic) analgesia.

[0133] Example 5: Exemplary preparation of magnesium-containing oxytocin peptide formulations Example 5A The drug product formulation, which is hypertonic and targets a pH of 4.5, consists of oxytocin USP (150 IU / mL); magnesium chloride USP (as the hexahydrate or anhydrous salt); citric acid USP (as the anhydrous or monohydrate form); sodium hydroxide NF; and sterile water for injection USP. The quantitative composition is provided in Table 1. All components meet the requirements of the corresponding monograph compendium (USP / NF). [Table 1]

[0134] The drug product is manufactured by dissolving the ingredients in sterile water for injection, sterile filtering, filling into snap-top vials in a preservative-free pump, and testing generally in accordance with the FDA's July 2002 nasal spray guidelines.

[0135] In one example, a 10 L batch of magnesium-containing oxytocin formulation according to the composition provided in Table 1 was prepared as follows: A formulation container was filled with water to approximately 60% of the required batch volume. With stirring at ambient temperature, the required amounts of sodium chloride, citric acid, and magnesium chloride hexahydrate were added in the following order: The materials dissolved readily. No heating was required, just gentle stirring. The pH of the solution was adjusted to 4.5 by adding 1 N NaOH (in case of over-titration, it can be back-titrated to pH 4.5 with 10% HCl). The required amount of oxytocin was added and stirred until dissolved. Water was added to bring the batch to the final weight / volume. The solution was stirred until homogeneous.

[0136] Example 5B The drug product formulation, which is isotonic and targets a pH of 4.5, consists of oxytocin USP (150 IU / mL); magnesium citrate, sodium chloride USP; sodium acetate trihydrate USP; glacial acetic acid USP; and sterile water for injection USP. The quantitative composition is provided in Table 2. The target pH of 4.5 is selected based on optimal formulation stability at or near pH 4.5 (Hawe et al., Pharmaceut. Res. 26:1679-1688 (2009)). All components meet the compendial requirements of the corresponding monographs (USP / NF).

[0137] To prepare oxytocin stock solution, add lyophilized oxytocin (2 mg) to 1 mL of water (USP), 0.9% saline, or phosphate-buffered saline in a 5 mL glass container. Stir the solution until all oxytocin is dissolved and adjust the pH to 3.5-8.5 to produce 1 mL of a 2 mg / mL (approximately 1000 IU / mL) liquid oxytocin formulation.

[0138] For use as clinical material, oxytocin and excipients are manufactured according to current Good Manufacturing Practice and terminally sterilized (sterile filtration through a 0.2 micron membrane filter) before being filled into glass storage bottles and sealed with a pump actuator. By increasing or decreasing the amount of oxytocin, various formulation concentrations can be generated from this example. This 1 mL batch volume yields approximately 10 doses of oxytocin. [Table 2]

[0139] Example 6: Treatment of chronic migraine and frequent episodic migraine with a magnesium-containing oxytocin peptide formulation Example 6A A subset of patients with frequent migraines was examined by headache specialists at a clinic in a large hospital in Southern California. The specialists gave the patients three nasal sprays, labeled A, B, and C, to take home. The patients then used one of the vials during each of three subsequent migraine episodes and rated the degree of pain relief they experienced as a result of the spray. The three vials contained enough liquid to deliver 48 milligrams of magnesium citrate adjuvant in a 12% solution (Vial A), 66 micrograms of oxytocin (Vial B), or 48 mg of magnesium citrate adjuvant plus 66 micrograms of oxytocin in a 12% solution (Vial C). Patients reported no benefit in terms of pain relief from Vial A, some benefit from Vial B, and significantly greater pain relief from Vial C. These results demonstrate the synergistic effect of oxytocin and the magnesium-containing adjuvant in relieving craniofacial pain.

[0140] Example 6B Ninety human patients suffering from migraines with or without aura will be enrolled in a randomized, double-blind, parallel study. Each subject will participate for 90 days. Stage 1 will include a 28-day baseline (screening) during which patients will record their headache occurrence and intake of standard medications. Stage 2 will be a 56-day period during which patients will take an intranasal oxytocin / magnesium citrate preparation when they experience a headache. Sixty patients will be assigned to the active group (oxytocin / magnesium preparation) and 30 to the placebo group.

[0141] Eligibility for this study will be determined by telephone interview and at the first visit at the research center. At the potential participant's first visit to the research center, a medical history will be taken and a physical examination will be performed. In particular, the diagnosis of chronic migraine with or without aura or frequent episodic migraine will be confirmed by a skilled practitioner. If participants meet the inclusion criteria and no exclusion criteria apply, written informed consent will be obtained. Demographic and medical data will be recorded.

[0142] The pain assessment tool is the VRS-4. This tool is self-reported and asks subjects to rank their pain level on a 4-category scale (severe, moderate, mild, none). Subjects enter their pain score using a secure, portable ePRO device. Subjects are trained to administer the VRS-4 using the portable device at the screening visit.

[0143] During the 28-day Stage 1 screening period (after subjects sign informed consent), subjects enter a headache (migraine or tension-type headache) pain score once daily. If a subject does not experience a headache on a given day, no pain score is entered. The number of migraine and / or tension-type headaches recorded during the screening period will be used to determine eligibility for the study. Patients who record 15 or more headache days per 28-day period will be included as chronic migraineurs; subjects who record 8 to 14 headache days per 28-day period will be enrolled as frequent episodic migraineurs.

[0144] In stage 1 and stage 2: On days when headache occurs, subjects will intranasally administer magnesium-containing oxytocin peptide formulation. Subjects will record pain scores at the time of headache onset, then 30 minutes after the first administration of study drug, and 1, 2, 3, 4, 5 and 6 hours later. On days when headache does not occur, subjects will not take study drug and will not record any pain scores.

[0145] To assess the analgesic efficacy of oxytocin / magnesium citrate preparations by comparing post-administration effects on reduction of pain intensity, latency to onset of analgesia, duration of analgesia and headache frequency compared to intranasal placebo treatment.

[0146] Example 7: Treatment of neck and shoulder pain with a high-dose oxytocin formulation A patient with chronic tension-type headache reported severe pain in the head, neck, and shoulders. The patient took four sprays of oxytocin at 7.5 IU / spray for a 30-unit dose, at which point the headache disappeared, but neck and shoulder pain persisted. The patient continued taking the medication and eventually took another 8 to 10 sprays, or a total of 60 to 75 IU, at which point the neck and shoulder pain subsided and ceased. Thus, a higher dose was required to affect the neck and shoulder pain than was required to inhibit headache in the same patient.

[0147] Example 8: Analgesic effect of nasal oxytocin on cervical nerve-related pain in a rat paw inflammation model The analgesic effect of intranasally administered oxytocin on cervical nerve-related inflammatory pain was evaluated in a rat paw inflammation model (Martin et al., Pain 1999, 82:199-205). One of three doses (193, 385, or 768 micrograms in 48 microliters) of oxytocin was administered intranasally, and withdrawal force thresholds in grams were measured after mechanical stimulation of the inflamed area (forepaw) at regular intervals over the next 3 hours and compared with those of rats treated with vehicle (phosphate-buffered saline). Freund's complete adjuvant was injected into the left forepaw of rats, resulting in intense inflammation in the paw and a substantial reduction in the force required to induce a withdrawal response (mechanical allodynia). The results are shown in Figure 8. The lowest dose of oxytocin was ineffective in elevating pain thresholds, whereas the two higher doses resulted in a statistically significant partial reversal of inflammation-induced mechanical allodynia. These results are consistent with nasal oxytocin being analgesic for pain associated with the cervical nerves.

[0148] The analgesic effect of magnesium-containing oxytocin peptide preparation on cervical nerve-related inflammatory pain is tested in rat paw inflammation model.A series of doses are administered according to the same procedure as above.The withdrawal threshold in grams is measured at regular intervals over a 24-hour period after intranasal administration of the preparation.

[0149] Example 9: Treatment of neck pain with a magnesium-containing oxytocin peptide formulation A 20-year-old female patient who had recently been involved in a traffic accident was suffering from severe neck pain. The patient was treated with the magnesium-containing oxytocin formulation of Example 5A. The patient's neck pain was measured on an 11-point pain-rating numerical scale. The patient was asked to assign a numerical value to her pain based on her internal perception. "1" is threshold pain, i.e., barely painful, and "10" is the worst pain the patient can imagine (zero on this scale means no pain). When 60 IU of oxytocin (contained in a 400 μL formulation) was applied to the patient's nose in four sprays of 100 μL per spray, the patient's neck pain decreased from a rating of "9" to a rating of "4" on the 11-point pain-rating numerical scale. The patient's pain relief occurred within 10 minutes of treatment.

[0150] The analgesic effect of magnesium-containing oxytocin preparations occurred more quickly than expected compared with oxytocin preparations that do not contain magnesium salts, which typically have a slower onset of analgesia. For example, in a study using a commercially available oxytocin preparation (Syntocinon®), substantial analgesia in chronic migraine headaches did not occur until 2 to 4 hours after administration (Yeomans et al., Cephalalgia 2013, 33(8 Supplement) 1-291, p. 59).

[0151] Illustrative Embodiments The present invention is further illustrated by the following embodiments, the features of each of which may be combined with any of the other embodiments as appropriate and permissible.

[0152] Embodiment 1. In one embodiment, the present invention provides a method for treating pain, comprising administering to a subject in need thereof effective doses of an oxytocin peptide and a magnesium salt, wherein co-administration of the oxytocin peptide and the magnesium salt results in synergistic analgesia.

[0153] Embodiment 2. In a further embodiment of Embodiment 1, the oxytocin peptide is administered simultaneously with the magnesium salt.

[0154] Embodiment 3. In a further embodiment of Embodiment 1, the oxytocin peptide is administered before or after administration of the magnesium salt.

[0155] Embodiment 4. In a further embodiment of any one of Embodiments 1-3, the oxytocin peptide is administered via craniofacial mucosal administration.

[0156] Embodiment 5. In a further embodiment of embodiment 4, the oxytocin peptide is administered via intranasal administration.

[0157] Embodiment 6. In a further embodiment of embodiment 5, the oxytocin peptide and the magnesium salt are administered via intranasal administration.

[0158] Embodiment 7. In a further embodiment of any one of Embodiments 1-6, the magnesium salt comprises magnesium chloride.

[0159] Embodiment 8. In a further embodiment of any one of Embodiments 1-7, the magnesium salt comprises magnesium citrate.

[0160] Embodiment 9. In a further embodiment of Embodiment 8, the effective dose of the oxytocin peptide is from about 0.5 μg to about 2000 μg.

[0161] Embodiment 10. In a further embodiment of Embodiment 8, the effective dose of the magnesium salt provides from about 50 μg to about 68 mg of magnesium.

[0162] Embodiment 11. In a further embodiment of Embodiment 8, the effective dose of the oxytocin peptide and the magnesium salt comprises about 15 μg to about 120 μg of the oxytocin peptide administered in an aqueous solution containing about 1.1% to about 1.6% (w / v) magnesium (or about 10% to about 14% (w / v) magnesium citrate).

[0163] Embodiment 12. In a further embodiment of Embodiment 8, the effective dose of the oxytocin peptide and the magnesium salt comprises about 66 μg (or about 60 μg) of the oxytocin peptide administered in an aqueous solution containing about 1.36% magnesium (or about 12% magnesium citrate).

[0164] Embodiment 13. In a further embodiment of any one of Embodiments 1 to 12, the pain is chronic pain.

[0165] Embodiment 14. In a further embodiment of any one of Embodiments 1 to 12, the pain is acute pain.

[0166] Embodiment 15. In a further embodiment of any one of Embodiments 1 to 12, the pain is incident pain.

[0167] Embodiment 16. In a further embodiment of any one of Embodiments 1-12, the pain is headache or facial pain.

[0168] Embodiment 17. In a further embodiment of any one of Embodiments 1 to 12, the pain is trigeminal nerve-associated pain.

[0169] Embodiment 18. In a further embodiment of any one of Embodiments 1 to 12, the pain is a migraine headache.

[0170] Embodiment 19. In a further embodiment of any one of Embodiments 1 to 12, the pain is neck pain (or occipital neuralgia), shoulder pain, or upper limb pain.

[0171] Embodiment 20. In a further embodiment of any one of Embodiments 1 to 12, the pain is cervical nerve-associated pain (or upper cervical nerve-associated pain).

[0172] Embodiment 21. In a further embodiment of any one of Embodiments 1 to 20, the oxytocin peptide is human oxytocin (SEQ ID NO: 1).

[0173] Embodiment 22. In one embodiment, the present invention provides a composition comprising an oxytocin peptide and a magnesium salt, wherein the oxytocin peptide and the magnesium salt are present in amounts that provide synergistic analgesia when used in the treatment of pain.

[0174] Embodiment 23. In a further embodiment of embodiment 22, the oxytocin peptide is human oxytocin (SEQ ID NO: 1).

[0175] Embodiment 24. In a further embodiment of embodiment 22 or 23, the magnesium salt comprises magnesium citrate and / or magnesium chloride.

[0176] Embodiment 25. In a further embodiment of embodiment 24, the magnesium salts include magnesium chloride and magnesium citrate.

[0177] Embodiment 26. In a further embodiment of any one of Embodiments 22-25, the composition is a liquid formulation comprising from about 0.01 mg / mL to about 16 mg / mL (or from about 5 IU / mL to about 8000 IU / mL) of the oxytocin peptide.

[0178] Embodiment 27. In a further embodiment of Embodiment 26, the liquid formulation comprises from about 0.15 mg / mL to about 1.5 mg / mL (or from about 75 IU / mL to about 750 IU / mL) of the oxytocin peptide.

[0179] Embodiment 28. In a further embodiment of any one of Embodiments 22-27, the composition is a liquid formulation comprising the magnesium salt in an amount providing from about 3 mg / mL to about 30 mg / mL of magnesium or from about 125 mM to about 1200 mM magnesium.

[0180] Embodiment 29. In a further embodiment of embodiment 28, the liquid formulation comprises from about 11 mg / mL to about 15 mg / mL of magnesium or from about 250 mM to about 600 mM of magnesium.

[0181] Embodiment 30. In a further embodiment of any one of Embodiments 22-29, the composition further comprises one or more excipients, vehicles, emulsifiers, stabilizers, preservatives, mucoadhesives, antimicrobial agents, buffers, and / or other additives.

[0182] Embodiment 31. In a further embodiment of any one of embodiments 22 to 29, the composition has a pH of about 4.5.

[0183] Embodiment 32. In a further embodiment of any one of Embodiments 22 to 31, the composition is suitable for nasal administration.

[0184] Embodiment 33. In a further embodiment of embodiment 32, the composition further comprises a device for intranasal administration.

[0185] Embodiment 34. In a further embodiment of embodiment 33, said device for intranasal administration is a nasal pump device.

[0186] Embodiment 35. In a further embodiment of embodiment 34, the nasal pump device comprises a reservoir bottle attached to a pump actuator.

[0187] Embodiment 36. In a further embodiment of embodiment 35, the pump actuator metered to deliver a specific volume of about 50 μL.

[0188] Embodiment 37. In a further embodiment of embodiment 34, the nasal pump device comprises a reservoir bottle attached to an aerosolizer.

[0189] Embodiment 38. In a further embodiment of any one of Embodiments 34 to 37, the nasal pump device comprises: (i) a filter to prevent backflow; (ii) metal-free flow paths, and (iii) Gamma-ray stable plastic materials It comprises one or more of the following:

[0190] Embodiment 39. In one embodiment, the present invention provides a method for treating pain, comprising administering to a subject in need of pain treatment an effective dose of a composition of any one of embodiments 22-32 and a pharmaceutically acceptable carrier.

[0191] Embodiment 40. In one embodiment, the present invention provides a kit comprising the composition of any one of embodiments 22-38 and packaging material.

[0192] Embodiment 41. In a further embodiment of embodiment 40, the kit further comprises instructions for administering the composition according to the method of embodiment 39.

[0193] Although the foregoing invention has been described in some detail for purposes of illustration and example, for purposes of clarity of understanding, it will be apparent to those skilled in the art that certain changes and modifications can be made without departing from the invention. Therefore, such descriptions and illustrations should not be construed as limiting the scope of the invention.

[0194] All patents, patent applications, documents and articles cited herein are incorporated by reference in their entirety.

Claims

1. A combination for treating pain comprising an effective dose of an oxytocin peptide and a magnesium salt capable of generating magnesium ions; the combination is formulated as a liquid formulation; the liquid formulation comprises about 0.01 mg / mL to about 16 mg / mL of the oxytocin peptide and about 1 mg / mL to 30 mg / mL of magnesium ions; and the liquid formulation is delivered via intranasal administration.

2. The combination described in claim 1, wherein the liquid formulation is an aqueous formulation.

3. A combination according to claim 1 or 2, wherein the magnesium salt comprises magnesium chloride.

4. A combination according to claim 1 or 2, wherein the magnesium salt comprises magnesium citrate.

5. The combination described in claim 1 or 2, wherein the liquid formulation contains about 0.1 mg / mL to about 4 mg / mL of the oxytocin peptide.

6. The combination described in claim 1 or 2, wherein the liquid formulation contains about 5 mg / mL to about 30 mg / mL of magnesium ions.

7. A combination described in any one of claims 1 to 6, wherein the pain is chronic pain.

8. A combination described in any one of claims 1 to 6, wherein the pain is acute pain.

9. A combination described in any one of claims 1 to 6, wherein the pain is incidental pain.

10. A combination described in any one of claims 1 to 6, wherein the pain is headache or facial pain.

11. A combination described in any one of claims 1 to 6, wherein the pain is trigeminal nerve-related pain.

12. A combination described in any one of claims 1 to 6, wherein the pain is a migraine.

13. A combination described in any one of claims 1 to 6, wherein the pain is neck pain, shoulder pain, or upper limb pain.

14. A combination described in any one of claims 1 to 6, wherein the pain is cervical nerve-related pain.

15. A combination described in any one of claims 1 to 14, wherein the oxytocin peptide is human oxytocin (sequence number 1).

16. The combination of any one of claims 1 to 15, wherein the liquid formulation further comprises a pharmaceutically acceptable carrier.

17. The combination of any one of claims 1 to 15, wherein the liquid formulation further comprises one or more excipients, vehicles, emulsifiers, stabilizers, preservatives, mucoadhesives, antibacterial agents, buffers and / or other additives.

18. The combination of any one of claims 1 to 17, wherein the liquid formulation has a pH of about 4.5.

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