Novel methods for treating gastroparesis

Abstract

Described herein are methods for treating gastroparesis with an intranasal composition containing metoclopramide, the methods including a period during which the patient is not administered a composition containing metoclopramide.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent No. 63 / 476,356, filed December 20, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Diabetic gastroparesis (DGP) is a chronic disease of the stomach characterized by delayed gastric emptying and prominent symptoms of nausea, vomiting, early satiety, bloating, and / or severe abdominal pain. In 2020, the FDA approved the first intranasal metoclopramide (MCP) outpatient treatment for patients with acute and recurrent DGP. However, updated methods to reduce unwanted side effects remain needed. The present disclosure addresses this unmet need. Summary of the Invention

[0003] The present disclosure provides a method for treating gastroparesis with an intranasally administered composition comprising metoclopramide, the method including a period of time during which the patient is not administered a composition comprising metoclopramide.

[0004] One aspect of the present disclosure is a method for treating chronic gastroparesis in a patient in need thereof, comprising: intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a first period of time; after the first period of time, not administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a second period of time; and after the second period of time, intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a third period of time.

[0005] Another embodiment of the present disclosure is a method for treating recurrent gastroparesis in a patient in need thereof. The method comprises intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof. In this embodiment, the patient has previously been intranasally administered a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a first period of time, and the patient has not been intranasally administered a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a second period of time after the first period of time.

[0006] A further aspect of this embodiment is a method for reducing the likelihood or probability that a patient will experience tardive dyskinesia due to metoclopramide therapy, comprising the steps of intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a first period of time, not administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a second period of time after the first period of time, and intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a third period of time after the second period of time.

[0007] A further aspect of this embodiment is a method for reducing the likelihood or probability that a patient will experience tardive dyskinesia due to metoclopramide therapy. The method includes intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof. In this embodiment, the patient has previously been intranasally administered a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a first period of time, and the patient has not been intranasally administered a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a second period of time after the first period of time.

[0008] In one aspect, the present disclosure provides a method for reducing the likelihood or probability that a patient will experience adverse reactions due to metoclopramide therapy. The method includes intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a first period of time; after the first period of time, not administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a second period of time; and after the second period of time, intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a third period of time. In this aspect, the adverse reactions are one or more of extrapyramidal effects, neuroleptic malignant syndrome, depression, hypertension, fluid retention, hyperprolactinemia, and inability to drive or operate machinery.

[0009] In another aspect, the present disclosure provides a method for reducing the likelihood or probability that a patient will experience side effects due to metoclopramide therapy. The method includes intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof. In this aspect, the patient has previously been administered a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof intranasally for a first period of time. The patient has also not been administered a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof intranasally for a second period of time after the first period of time, and the adverse reaction is one or more of extrapyramidal effects, neuroleptic malignant syndrome, depression, hypertension, fluid retention, hyperprolactinemia, and inability to drive or operate machinery.

[0010] In embodiments, the method may include a third, fourth, fifth, sixth, or seventh period similar to the first or second period described above.

[0011] In embodiments, the patient is a human, e.g., a female human. In various embodiments, the patient, e.g., a female patient, has diabetic gastroparesis.

[0012] In various embodiments, the reduced likelihood or probability is at least a 10% reduced likelihood or probability, at least a 20% reduced likelihood or probability, at least a 30% reduced likelihood or probability, at least a 40% reduced likelihood or probability, at least a 50% reduced likelihood or probability, at least a 60% reduced likelihood or probability, at least a 70% reduced likelihood or probability, at least an 80% reduced likelihood or probability, or at least a 90% reduced likelihood or probability. In some cases, the reduced likelihood or probability is at least a 1-fold reduced likelihood or probability, at least a 2-fold reduced likelihood or probability, at least a 3-fold reduced likelihood or probability, at least a 4-fold reduced likelihood or probability, at least a 5-fold reduced likelihood or probability, at least a 6-fold reduced likelihood or probability, at least a 7-fold reduced likelihood or probability, at least an 8-fold reduced likelihood or probability, at least a 9-fold reduced likelihood or probability, or at least a 10-fold reduced likelihood or probability.

[0013] In embodiments, the patient does not experience tardive dyskinesia syndrome during administration of the method. In some embodiments, the patient does not experience symptoms of an adverse reaction during administration of the method. In these embodiments, the adverse reaction is one or more of extrapyramidal effects, neuroleptic malignant syndrome, depression, hypertension, fluid retention, hyperprolactinemia, and inability to drive or operate machinery.

[0014] Furthermore, any composition or method disclosed herein is applicable to any other composition or method disclosed herein, that is, any aspect or embodiment described herein can be combined with any other aspect or embodiment disclosed herein. DETAILED DESCRIPTION OF THE INVENTION

[0015] The present disclosure provides a method for treating gastroparesis with an intranasally administered composition comprising metoclopramide, the method including a period of time during which the patient is not administered a composition comprising metoclopramide.

[0016] Gastroparesis and symptoms of gastroparesis Described herein are methods for treating gastroparesis and its symptoms. Gastroparesis can be described as a disorder that slows or stops the movement of food from the stomach to the small intestine. If a subject is exhibiting or has previously exhibited symptoms of gastroparesis, the subject may be suspected of having gastroparesis. Specific symptoms of gastroparesis are selected from the group consisting of nausea (upset stomach with the urge to vomit or vomit), retching (feeling like you're going to vomit but nothing comes out), vomiting, gastric distension, inability to finish a normal amount of food, excessive fullness after eating, loss of appetite, flatulence, a visibly enlarged stomach or abdomen, and epigastric (above the belly button) pain or discomfort. Some embodiments relate to a method of treating two, three, four, five, six, seven, eight, nine, ten, or eleven of the symptoms selected from the group consisting of nausea (upset stomach with urge to vomit or vomit), retching (feeling like you're going to vomit but nothing comes out), vomiting, stomach bloating, inability to finish a normal amount of food, excessive fullness after eating, loss of appetite, flatulence, visibly enlarged stomach or abdomen, epigastric pain (above the belly button), and epigastric discomfort (above the belly button), hi some embodiments, the gastroparesis is diabetic gastroparesis.

[0017] In some embodiments, the patient in need of treatment has symptoms of nausea, bloating, vomiting, delayed vomiting, early satiety, diarrhea, fullness, loss of appetite, stomach bloating, visibly large stomach, and upper abdominal discomfort, which in some cases are associated with diabetic gastroparesis.

[0018] Treatment with intranasal metoclopramide As used herein, "metoclopramide" refers to metoclopramide in a solution formulation containing a salt of metoclopramide. When quantifying the mass of metoclopramide herein, unless otherwise specified, all masses of metoclopramide refer to the mass of the free base, which has a molecular weight of 299.80. One method for producing metoclopramide is described in U.S. Pat. No. 3,177,252, the entire contents of which are incorporated herein by reference. Therefore, as used herein, unless otherwise specified, the term "metoclopramide" includes the free base of metoclopramide (4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide) and pharmaceutically acceptable salts of metoclopramide free base. When the "free base" or a specific salt of metoclopramide is intended, it is so designated. A particularly preferred form of metoclopramide is metoclopramide hydrochloride.

[0019] In some embodiments, the composition comprising metoclopramide, or a pharmaceutically acceptable salt thereof, further comprises benzalkonium chloride. In some embodiments, the composition has a benzalkonium chloride concentration of about 0.005% (w / v) to about 0.05% (w / v). The benzalkonium chloride may be at a concentration of about 0.02% to about 0.04% (w / v), e.g., about 0.02% to about 0.03% (w / v). In some embodiments, the benzalkonium chloride is at a concentration of at least about 0.025% (w / v), or the benzalkonium chloride is at a concentration of about 0.025% (w / v).

[0020] In some embodiments, the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof further comprises benzyl alcohol. The benzyl alcohol may be at a concentration of about 0.01% (w / v) to about 1% (w / v). In some cases, the benzyl alcohol may be at a concentration of about 0.75% (w / v).

[0021] In a different embodiment, the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof further comprises a buffering agent, such as citrate / phosphate, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleate, McIlvaine, phosphate, Prideaux-Ward, succinate, citrate-phosphate-borate (Teorell-Stanhagen), valonal acetate, IVIES (2-(N-morpholino)ethanesulfonic acid), BIS-TRIS (bis(2-hydroxyethyl)iminotris(hydroxymethyl)methane), ADA ( N-(2-acetamido)-2-iminodiacetic acid), ACES (N-(carbamoylmethyl)-2-aminoethanesulfonic acid), PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid)), MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid), BIS-TRIS propane (1,3-bis(tris(hydroxymethyl)methylamino)propane), BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid), MOPS (3-(N-morpholino)-2-hydroxypropanesulfonic acid) N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid), TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES (N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid)), DIPSO (3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropanesulfonic acid), MOBS (4-(N-morpholino)butanesulfonic acid), TAPSO (3-(N-tris(hydroxymethyl)methylamino)-2-hydroxypropanesulfonic acid), Tris(N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), (hydroxymethyl)aminomethane, HEPPSO (N-(2-hydroxyethyl)piperazine-N'-(2-hydroxypropanesulfonic acid)), POPSO (piperazine-N,N'-bis(2-hydroxypropanesulfonic acid)), TEA (triethanolamine), EPPS (N-(2-hydroxyethyl)piperazine-N'-(3-propanesulfonic acid)), TWINE (N-tris(hydroxymethyl)methylglycine), GLY-GLY (glycylglycine), BICINE (N,N-bis(2-hydroxyethyl)glycine), HEPBS (N-(2-hydroxyethyl)piperazine-N'-(4-butanesulfonic acid)), TAPS (N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid), and AMPD (2-amino-2-methyl-1,3-propanediol) buffers.

[0022] In some embodiments, the buffer comprises a citrate buffer. The citrate buffer may comprise a combination of citric acid monohydrate and sodium citrate dihydrate. In some cases, the citric acid monohydrate is present in an amount of about 0.2% to about 0.5% w / v, about 0.25% to about 0.4% w / v, or about 0.3% to about 0.35% w / v, and the sodium citrate dihydrate is present in an amount of about 1.0 to about 1.8% w / v, about 1.2 to about 1.6% w / v, or about 1.3 to about 1.5% w / v. The combined amount of citric acid monohydrate and sodium citrate dihydrate in the composition may be less than about 2.3% w / v. In various cases, the citric acid monohydrate is present in an amount of about 0.1% and the sodium citrate dihydrate is present in an amount of about 0.44%. In some cases, the composition provides a citrate concentration of at least about 10 millimolar.

[0023] In some cases, the buffer comprises sodium acetate.

[0024] In embodiments, the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof has a pH greater than about 4.5, e.g., the composition has a pH greater than about 4.6, or the composition has a pH greater than about 5.0.

[0025] In some embodiments, the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof further comprises at least one member of the group consisting of a salt, edetate disodium dihydrate (EDTA), sorbitol, a sugar, and a flavoring agent.

[0026] In various embodiments, the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof is substantially free of additional antioxidants.

[0027] In some embodiments, a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof has an osmolality of about 500 mOsm / kg to about 1400 mOsm / kg.

[0028] In some embodiments, the composition containing metoclopramide or a pharmaceutically acceptable salt thereof comprises benzalkonium chloride, citric acid monohydrate, edetate disodium dihydrate (EDTA), purified water, sodium citrate dihydrate, and sorbitol. In some cases, each 70 μL aliquot of the composition contains 15 mg of metoclopramide or a pharmaceutically acceptable salt thereof, each 70 μL aliquot of the composition contains 7.5 mg of metoclopramide or a pharmaceutically acceptable salt thereof, or each 35 μL aliquot of the composition contains 7.5 mg of metoclopramide. In various cases, the composition has a pH of about 5.5. The composition may have a citrate concentration of at least about 10 millimolar ([citrate] = [citric acid] + [dihydrogen citrate ion] + [hydrogen citrate ion] + [citrate ion]).

[0029] In some embodiments, the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof comprises benzyl alcohol, citric acid monohydrate, edetate disodium dihydrate (EDTA), purified water, sodium citrate dihydrate, and sorbitol. In some embodiments, the composition comprises less than about 1% w / v benzyl alcohol.

[0030] In various embodiments, a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof comprises benzyl alcohol, acetate buffer, edetate disodium dihydrate (EDTA), purified water, and sorbitol.

[0031] In some embodiments, compositions comprising metoclopramide or a pharmaceutically acceptable salt thereof exhibit a mean percent change in optical density (OD) of less than about 2% per week of 200 mg / mL of metoclopramide when stored at a temperature of 40° C. and a relative humidity of 75%. In some cases, the mean percent change in optical density (OD) is less than about 1.8% OD per week.

[0032] In some embodiments, the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof has a shelf life of at least about 8 weeks at a temperature of about 40° C. <631> It is a nasal solution that remains clear to pale yellow when compared to standard E.

[0033] In some embodiments, methods include treating gastroparesis, including moderate to severe gastroparesis of various etiologies, including gastroparesis due to, associated with, or caused by diabetes (including types 1 and 2), post-viral syndrome, anorexia nervosa, gastric or vagus nerve surgery, medications such as anticholinergics and narcotics that tend to inhibit intestinal and gastric contractions, esophageal reflux disease, smooth muscle diseases (e.g., amyloidosis and scleroderma), nervous system diseases (including abdominal migraine and Parkinson's disease), and / or metabolic diseases (including hypothyroidism). In certain embodiments, the gastroparesis is moderate gastroparesis. In some embodiments, the gastroparesis is severe gastroparesis. In various embodiments, the patient is a female human, e.g., a female human with diabetes.

[0034] In some embodiments, nasal metoclopramide is administered in the absence of other gastroparesis drugs. In some embodiments, additional drugs may be administered as needed. In some embodiments, the treatment methods provided herein may also include co-administration of one or more additional therapeutic agents with the nasal metoclopramide formulations described herein. The additional therapeutic agents may be administered simultaneously with metoclopramide or at separate time intervals. In some embodiments, one or more other drugs may be added to the nasal metoclopramide formulation. Additional therapeutic agents may include painkillers, insulin, and other drugs useful in managing diabetes, steroids, particularly steroids that prevent nasal irritation, and antidepressants.

[0035] Various methods for assessing the severity of gastroparesis and gastric emptying can be used and are well known to those skilled in the art. Such methods include questioning patients about their gastroparesis symptoms using a patient-reported outcome (PRO) symptom instrument. Techniques such as the octanoic acid breath test, wireless capsule endoscopy, radioscintigraphy, ultrasound, and x-rays using radiopaque markers such as barium can be used.

[0036] In embodiments, the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof is administered in at least two aliquots per day, e.g., the composition is administered in three aliquots per day, or the composition is administered in four aliquots per day.

[0037] In some embodiments, a composition comprising metoclopramide, or a pharmaceutically acceptable salt thereof, is administered as an intranasal spray.

[0038] In some embodiments, an aliquot of a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof has a volume of about 25 μL to about 140 μL, e.g., an aliquot of a composition has a volume of about 50 μL, and an aliquot of a composition has a volume of about 70 μL.

[0039] In various embodiments, a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof is administered as one spray into one nostril or one spray into each nostril about 15 minutes to about 1 hour before a meal. The composition can also be administered as one spray into one nostril about 20 minutes to about 45 minutes before a meal. Optionally, the composition is administered as one spray into one or each nostril about 30 minutes before a meal.

[0040] Administration can be prescribed 30 minutes before meals, assuming three meals per day, and before bedtime. In some embodiments, doses are administered before breakfast and dinner. In some embodiments, each dose is administered as a single intranasal aliquot (e.g., spray). In some embodiments, each dose is administered as two aliquots (e.g., one spray per nostril). The nasal metoclopramide compositions described herein can be administered to a patient, e.g., a human female patient, as one spray into one nostril four times daily (one spray four times daily for about 1, 2, 3, 4, 5, 6, 7, or 8 weeks) or one spray into each nostril four times daily (two sprays four times weekly for about 1, 2, 3, 4, 5, 6, 7, or 8 weeks).

[0041] In some embodiments, the composition has a concentration of metoclopramide or a pharmaceutically acceptable salt thereof of about 20.0% (w / v) to about 30.0% (w / v). The composition can contain 5 mg to 25 mg of metoclopramide or a pharmaceutically acceptable salt thereof per aliquot. In some cases, the metoclopramide composition comprises administering about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg of metoclopramide or a pharmaceutically acceptable salt thereof per aliquot. Metoclopramide or a pharmaceutically acceptable salt thereof may be administered at a dose of 20 mg to 100 mg per day, metoclopramide or a pharmaceutically acceptable salt thereof may be administered at a dose of 30 mg to 80 mg per day, metoclopramide or a pharmaceutically acceptable salt thereof may be administered at a dose of 30 mg to 60 mg per day, or metoclopramide or a pharmaceutically acceptable salt thereof may be administered at a dose of 30 mg to 45 mg per day.

[0042] For example, a dose of about 0.1 mg / kg to about 2.5 mg / kg can be administered to a patient with gastroparesis. Exemplary dosages can be about 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2.0 mg / kg, 2.1 mg / kg, 2.2 mg / kg, 2.3 mg / kg, 2.4 mg / kg, or 2.5 mg / kg. In some embodiments, the intranasal dosage is about 0.06 to about 1.2 mg / kg of body weight. In some embodiments, the intranasal dose is about 0.06 mg / kg, 0.08 mg / kg, 1.0 mg / kg, 1.2 mg / kg, and 1.4 mg / kg.

[0043] The weight of the patient may affect the dosage to be administered, and it will be well within the skill of the art to modify or titrate the dosage to obtain optimal efficacy as tolerated by the patient.

[0044] In some embodiments, a physician prescribes a lower dose of metoclopramide due to an underlying disease or other clinical considerations. For example, in the case of renal impairment, the physician prescribes a dose commensurate with the degree of renal impairment or other reasons for slowing the metabolism or clearance of metoclopramide, e.g., a 25% to 75% lower dose, and in some embodiments, a 50% lower dose than would be prescribed for a patient without renal impairment. In some such embodiments, the daily dose is 20 mg, administered as two intranasal doses, e.g., one before breakfast and one before dinner. In some embodiments, each dose is administered as a single intranasal aliquot (e.g., spray). In some embodiments, each dose is administered as two intranasal aliquots (e.g., two sprays, one into each nostril).

[0045] The above dosages for the treatment and management of gastroparesis can be administered before meals and / or before bedtime. In some embodiments, each dose is administered as a single intranasal aliquot (e.g., one spray into each nostril). In some embodiments, the dose can be divided into two or more intranasal aliquots (e.g., two sprays, one spray into each nostril).

[0046] Methods for avoiding or reducing the likelihood of experiencing side effects associated with metoclopramide The present disclosure provides a method for treating gastroparesis with an intranasally administered composition comprising metoclopramide, the method including a period of time during which the patient is not administered a composition comprising metoclopramide.

[0047] One aspect of the present disclosure is a method for treating chronic gastroparesis in a patient in need thereof, comprising: intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a first period of time; after the first period of time, not administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a second period of time; and after the second period of time, intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a third period of time.

[0048] Another embodiment of the present disclosure is a method for treating recurrent gastroparesis in a patient in need thereof. The method comprises intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof. In this embodiment, the patient has previously been intranasally administered a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a first period of time, and the patient has not been intranasally administered a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a second period of time after the first period of time.

[0049] A further aspect of this embodiment is a method for reducing the likelihood or probability that a patient will experience tardive dyskinesia due to metoclopramide therapy, comprising the steps of intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a first period of time, not administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a second period of time after the first period of time, and intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a third period of time after the second period of time.

[0050] A further aspect of this embodiment is a method for reducing the likelihood or probability that a patient will experience tardive dyskinesia due to metoclopramide therapy. The method includes intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof. In this embodiment, the patient has previously been intranasally administered a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a first period of time, and the patient has not been intranasally administered a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a second period of time after the first period of time.

[0051] In one aspect, the present disclosure provides a method for reducing the likelihood or probability that a patient will experience an adverse reaction due to metoclopramide therapy. The method includes intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a first period of time; after the first period of time, not administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a second period of time; and after the second period of time, intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a third period of time. In this aspect, the adverse reaction is one or more of extrapyramidal effects, neuroleptic malignant syndrome, depression, hypertension, fluid retention, hyperprolactinemia, and inability to drive or operate machinery.

[0052] In another aspect, the present disclosure provides a method for reducing the likelihood or probability that a patient will experience side effects due to metoclopramide therapy. The method includes intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof. In this aspect, the patient has previously been administered a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof intranasally for a first period of time. The patient has also not been administered a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof intranasally for a second period of time after the first period of time, and the adverse reaction is one or more of extrapyramidal effects, neuroleptic malignant syndrome, depression, hypertension, fluid retention, hyperprolactinemia, and inability to drive or operate machinery.

[0053] In embodiments, the method may include a third, fourth, fifth, sixth, or seventh period similar to the first or second period described above.

[0054] In some embodiments, the sum of the first period and the third period is greater than 12 weeks.

[0055] In some embodiments, the first period of time is greater than 12 weeks and / or the third period of time is greater than 12 weeks.

[0056] In various embodiments, the first period of time is from about 2 weeks to about 8 weeks and / or the third period of time is from about 2 weeks to about 8 weeks.

[0057] In some embodiments, the second period of time is at least 5 days, at least 6 days, or at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 12 days, at least 13 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 1 year.

[0058] In some embodiments, the method further includes not administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a fourth period of time following the third period of time, which can be at least 5 days, at least 6 days, or at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 12 days, at least 13 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 1 year.

[0059] In some cases, the method further includes intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a fifth period of time following the fourth period of time. The fourth period of time can be at least 5 days, at least 6 days, or at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 12 days, at least 13 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 1 year. The fifth period of time can be longer than 12 weeks, or the fifth period of time can be from about 2 weeks to about 8 weeks.

[0060] In various embodiments, the method further includes not administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a sixth period of time following the fifth period of time. The fifth period of time may be longer than 12 weeks, or the fifth period of time may be from about 2 weeks to about 8 weeks. The sixth period of time may be at least 5 days, at least 6 days, or at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 12 days, at least 13 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 1 year.

[0061] In some cases, the method further includes intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a seventh period of time following the sixth period of time. The sixth period of time can be at least 5 days, at least 6 days, or at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 12 days, at least 13 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 1 year. The seventh period of time can be longer than 12 weeks, or the seventh period of time can be from about 2 weeks to about 8 weeks.

[0062] In some embodiments, the method is performed for more than 12 weeks. In some cases, the method is performed for more than 6 months, for more than 1 year, for more than 2 years, for more than 3 years, for more than 4 years, or for more than 5 years.

[0063] In various embodiments, reducing the likelihood or probability is at least a 10% decrease in likelihood or probability compared to a method lacking at least the second period of time.

[0064] In various embodiments, reducing the likelihood or probability is at least a 10% decrease in likelihood or probability compared to a method lacking at least a fourth period of time.

[0065] In various embodiments, reducing the likelihood or probability is at least a 10% decrease in likelihood or probability compared to a method lacking at least a sixth period of time.

[0066] In some embodiments, the composition comprising metoclopramide, or a pharmaceutically acceptable salt thereof, further comprises benzalkonium chloride. In some embodiments, the composition has a benzalkonium chloride concentration of about 0.005% (w / v) to about 0.05% (w / v). The benzalkonium chloride may be at a concentration of about 0.02% to about 0.04% (w / v), e.g., about 0.02% to about 0.03% (w / v). In some embodiments, the benzalkonium chloride is at a concentration of at least about 0.025% (w / v), or the benzalkonium chloride is at a concentration of about 0.025% (w / v).

[0067] In some embodiments, the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof further comprises benzyl alcohol. The benzyl alcohol may be at a concentration of about 0.01% (w / v) to about 1% (w / v). In some cases, the benzyl alcohol may be at a concentration of about 0.75% (w / v).

[0068] In a different embodiment, the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof further comprises a buffering agent, such as citrate / phosphate, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleate, McIlvaine, phosphate, Prideaux-Ward, succinate, citrate-phosphate-borate (Teorell-Stanhagen), valonal acetate, IVIES (2-(N-morpholino)ethanesulfonic acid), BIS-TRIS (bis(2-hydroxyethyl)iminotris(hydroxymethyl)methane), ADA ( N-(2-acetamido)-2-iminodiacetic acid), ACES (N-(carbamoylmethyl)-2-aminoethanesulfonic acid), PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid)), MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid), BIS-TRIS propane (1,3-bis(tris(hydroxymethyl)methylamino)propane), BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid), MOPS (3-(N-morpholino)-2-hydroxypropanesulfonic acid) N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid), TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES (N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid)), DIPSO (3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropanesulfonic acid), MOBS (4-(N-morpholino)butanesulfonic acid), TAPSO (3-(N-tris(hydroxymethyl)methylamino)-2-hydroxypropanesulfonic acid), Tris(N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), (hydroxymethyl)aminomethane, HEPPSO (N-(2-hydroxyethyl)piperazine-N'-(2-hydroxypropanesulfonic acid)), POPSO (piperazine-N,N'-bis(2-hydroxypropanesulfonic acid)), TEA (triethanolamine), EPPS (N-(2-hydroxyethyl)piperazine-N'-(3-propanesulfonic acid)), TWINE (N-tris(hydroxymethyl)methylglycine), GLY-GLY (glycylglycine), BICINE (N,N-bis(2-hydroxyethyl)glycine), HEPBS (N-(2-hydroxyethyl)piperazine-N'-(4-butanesulfonic acid)), TAPS (N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid), and AMPD (2-amino-2-methyl-1,3-propanediol) buffers.

[0069] In some embodiments, the buffer comprises a citrate buffer. The citrate buffer may comprise a combination of citric acid monohydrate and sodium citrate dihydrate. In some cases, the citric acid monohydrate is present in an amount of about 0.2% to about 0.5% w / v, about 0.25% to about 0.4% w / v, or about 0.3% to about 0.35% w / v, and the sodium citrate dihydrate is present in an amount of about 1.0 to about 1.8% w / v, about 1.2 to about 1.6% w / v, or about 1.3 to about 1.5% w / v. The combined amount of citric acid monohydrate and sodium citrate dihydrate in the composition may be less than about 2.3% w / v. In various cases, the citric acid monohydrate is present in an amount of about 0.1% and the sodium citrate dihydrate is present in an amount of about 0.44%. In some cases, the composition provides a citrate concentration of at least about 10 millimolar.

[0070] In some cases, the buffer comprises sodium acetate.

[0071] In embodiments, the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof has a pH greater than about 4.5, e.g., the composition has a pH greater than about 4.6, or the composition has a pH greater than about 5.0.

[0072] In some embodiments, the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof further comprises at least one member of the group consisting of a salt, edetate disodium dihydrate (EDTA), sorbitol, a sugar, and a flavoring agent.

[0073] In various embodiments, the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof is substantially free of additional antioxidants.

[0074] In some embodiments, the composition has a concentration of metoclopramide or a pharmaceutically acceptable salt thereof of about 20.0% (w / v) to about 30.0% (w / v). The composition can contain 5 mg to 25 mg of metoclopramide or a pharmaceutically acceptable salt thereof per aliquot. In some cases, the metoclopramide composition comprises administering about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg of metoclopramide or a pharmaceutically acceptable salt thereof per aliquot. Metoclopramide or a pharmaceutically acceptable salt thereof may be administered at a dose of 20 mg to 100 mg per day, metoclopramide or a pharmaceutically acceptable salt thereof may be administered at a dose of 30 mg to 80 mg per day, metoclopramide or a pharmaceutically acceptable salt thereof may be administered at a dose of 30 mg to 60 mg per day, or metoclopramide or a pharmaceutically acceptable salt thereof may be administered at a dose of 30 mg to 45 mg per day.

[0075] In embodiments, the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof is administered in at least two aliquots per day, e.g., the composition is administered in three aliquots per day, or the composition is administered in four aliquots per day.

[0076] In some embodiments, a composition comprising metoclopramide, or a pharmaceutically acceptable salt thereof, is administered as an intranasal spray.

[0077] In some embodiments, an aliquot of a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof has a volume of about 25 μL to about 140 μL, e.g., an aliquot of a composition has a volume of about 50 μL, and an aliquot of a composition has a volume of about 70 μL.

[0078] In various embodiments, a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof is administered as one spray into one nostril or one spray into each nostril about 15 minutes to about 1 hour before a meal. The composition can also be administered as one spray into one nostril about 20 minutes to about 45 minutes before a meal. Optionally, the composition is administered as one spray into one or each nostril about 30 minutes before a meal.

[0079] In some embodiments, a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof has an osmolality of about 500 mOsm / kg to about 1400 mOsm / kg.

[0080] In some embodiments, the composition containing metoclopramide or a pharmaceutically acceptable salt thereof comprises benzalkonium chloride, citric acid monohydrate, edetate disodium dihydrate (EDTA), purified water, sodium citrate dihydrate, and sorbitol. In some cases, each 70 μL aliquot of the composition contains 15 mg of metoclopramide or a pharmaceutically acceptable salt thereof, each 70 μL aliquot of the composition contains 7.5 mg of metoclopramide or a pharmaceutically acceptable salt thereof, or each 35 μL aliquot of the composition contains 7.5 mg of metoclopramide. In various cases, the composition has a pH of about 5.5. The composition may have a citrate concentration of at least about 10 millimolar ([citrate] = [citric acid] + [dihydrogen citrate ion] + [hydrogen citrate ion] + [citrate ion]).

[0081] In some embodiments, the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof comprises benzyl alcohol, citric acid monohydrate, edetate disodium dihydrate (EDTA), purified water, sodium citrate dihydrate, and sorbitol. In some embodiments, the composition comprises less than about 1% w / v benzyl alcohol.

[0082] In various embodiments, a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof comprises benzyl alcohol, acetate buffer, edetate disodium dihydrate (EDTA), purified water, and sorbitol.

[0083] In some embodiments, compositions comprising metoclopramide or a pharmaceutically acceptable salt thereof exhibit a mean percent change in optical density (OD) of less than about 2% per week of 200 mg / mL of metoclopramide when stored at a temperature of 40° C. and a relative humidity of 75%. In some cases, the mean percent change in optical density (OD) is less than about 1.8% OD per week.

[0084] In some embodiments, the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof has a shelf life of at least about 8 weeks at a temperature of about 40° C. <631> It is a nasal solution that remains clear to pale yellow when compared to standard E.

[0085] In some embodiments, the patient does not experience tardive dyskinesia syndrome during the performance of the method.

[0086] In various embodiments, the patient does not experience symptoms of an adverse reaction during the method, in which the adverse reaction is one or more of extrapyramidal effects, neuroleptic malignant syndrome, depression, hypertension, fluid retention, hyperprolactinemia, and inability to drive or operate machinery.

[0087] In embodiments, the patient is a human, e.g., a female human. In various embodiments, the patient, e.g., a female patient, has diabetic gastroparesis.

[0088] In embodiments, the patient in need of treatment has symptoms of nausea, bloating, vomiting, delayed vomiting, early satiety, vomiting, fullness, loss of appetite, stomach bloating, visibly large stomach, and upper abdominal discomfort, which in some cases are associated with diabetic gastroparesis.

[0089] In some embodiments, the reduced likelihood or probability is at least a 10% reduced likelihood or probability, at least a 20% reduced likelihood or probability, at least a 30% reduced likelihood or probability, at least a 40% reduced likelihood or probability, at least a 50% reduced likelihood or probability, at least a 60% reduced likelihood or probability, at least a 70% reduced likelihood or probability, at least an 80% reduced likelihood or probability, or at least a 90% reduced likelihood or probability. In some cases, the reduced likelihood or probability is at least a 1-fold reduced likelihood or probability, at least a 2-fold reduced likelihood or probability, at least a 3-fold reduced likelihood or probability, at least a 4-fold reduced likelihood or probability, at least a 5-fold reduced likelihood or probability, at least a 6-fold reduced likelihood or probability, at least a 7-fold reduced likelihood or probability, at least an 8-fold reduced likelihood or probability, at least a 9-fold reduced likelihood or probability, or at least a 10-fold reduced likelihood or probability.

[0090] Nasal formulation manufacturing Nasal metoclopramide compositions can be prepared for administration as a medication to a patient for one of the indications described herein. In some embodiments, the nasal metoclopramide formulation is one described in U.S. Pat. No. 8,334,281, the entire contents of which are incorporated herein by reference. Briefly, metoclopramide, a buffer, benzalkonium chloride, and optional other ingredients (such as sodium chloride or other osmolality adjusters, sorbitol or other sweeteners, flavoring agents, etc.) can be combined to form a volume smaller than the desired final volume of the solution. The components can then be mixed until all components are dissolved. The pH can then be adjusted, if necessary, by adding an appropriate acid or base, e.g., HCl, NaOH, or a complementary acid or base of the buffer. Once the desired pH is achieved, the solution can then be made up to volume with water. The resulting solution can then be packaged in a container suitable for transport and distribution. In some embodiments, a suitable container includes a nasal pump, as described in more detail below. In other embodiments, a suitable container may be a vial, such as an amber glass vial, a glass ampoule, a glass bottle fitted with an inert rubber septum and a crimp cap top, or another suitable pharmaceutical vial.

[0091] To address the harmful effects of light on metoclopramide, manufacturers may conveniently include a container, particularly an opaque container, i.e., a container that is at least partially or completely light-resistant. In some embodiments, a suitable opaque container is brown or amber, particularly brown or amber glass. In other embodiments, the opaque container is an opaque polymeric container, such as those commonly used in the pharmaceutical field.

[0092] Some embodiments described herein provide a combination of a stable, clear, and / or colorless solution of metoclopramide and a means for intranasal administration of the metoclopramide solution as an article of manufacture. In some embodiments, the article of manufacture includes one of the metoclopramide solutions described herein and an intranasal administration device including a reservoir containing the metoclopramide solution, a pump in fluid communication with the reservoir, and a nozzle in fluid communication with the pump. During use, the pump is actuated to draw a measured amount of metoclopramide solution from the reservoir and eject the solution from the nozzle as an aerosolized spray. Suitable nasal administration devices are commercially available. Among suppliers of nasal administration devices that can be combined with the stable, substantially clear, and / or substantially colorless metoclopramide solution according to the present invention are Aptar (Vallois of America, Congers, New York) and Pfeiffer of America (Princeton, NJ). In some embodiments, the intranasal administration device is partially or completely opaque to protect the contents of the device from exposure to ambient light.

[0093] As used herein, a "nasal administration device" refers to a device capable of administering a metoclopramide-containing composition into a patient's nose at a predetermined dose. In some embodiments, the nasal administration device is an atomizer, comprising a reservoir configured to contain a metoclopramide solution and a pump configured to draw a predetermined amount of metoclopramide solution from the reservoir and dispense the predetermined amount of metoclopramide solution through an atomizing nozzle into at least one of the patient's nostrils. Suitable nasal administration devices are commercially available.

[0094] As used herein, the term "spray" refers to the volume of atomized liquid ejected from the nozzle of a nasal administration device upon a single actuation of the nasal administration device. Typically, each spray is administered into a single nostril of a patient. Thus, as used herein, a "spray" is a type of "aliquot," which is a general term referring to the amount of liquid sprayed, dripped, or otherwise introduced into the nostril of a subject, such as a patient.

[0095] Stability of intranasal compositions of metoclopramide. The compositions described herein comprise metoclopramide or a pharmaceutically acceptable salt thereof in a stable composition. In some embodiments described herein, a stable metoclopramide solution is a metoclopramide-containing solution characterized by the color stability or clarity of the solution. In some embodiments, color stability refers to the tendency of a formulated solution to maintain the same color as when initially formulated or to be colorless when stored for a specified period of time. In some embodiments, stability refers to the tendency of a formulated solution to maintain the same clarity as when initially formulated when stored for a specified period of time. In some embodiments, stability refers to the tendency of a formulated solution to resist degradation of one or more components, particularly metoclopramide, during storage. In some embodiments, such compositions are stable at temperatures ranging from about 5° C. to about 25° C. for periods of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, about 9 months, at least about 12 months, at least about 15 months, at least about 18 months, at least about 21 months, or at least about 24 months. In some embodiments, long-term stability at 5° C. to 25° C. can be simulated under accelerated conditions, e.g., at a temperature ranging from about 35° C. to about 60° C., particularly from about 35° C. to about 45° C., e.g., about 40° C. Thus, in some embodiments, the nasal metoclopramide compositions provided herein are stable upon storage under accelerated conditions, e.g., from about 25°C to about 60°C, particularly from about 30°C to about 50°C, from about 35°C to about 45°C, or about 40°C, for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 9 weeks, at least about 12 weeks, at least about 15 weeks, at least about 18 weeks, at least about 21 weeks, or at least about 24 weeks.

[0096] Stability can be measured by methods well known in the art, such as those specified by the United States Pharmacopeia (USP). Specifically, USP 26, pages 500-502 and 2138-2140 (incorporated herein by reference) provide general procedures for preparing standard color solutions for color determination and determining the color or colorlessness of the solutions. Therefore, those skilled in the art will be familiar with how to prepare standard solutions and compare the color of the compositions of the present invention with the standard solutions. 32 USP <631> , pages 238-239 (incorporated herein by reference) provides standard methods for determining the stability of metoclopramide in injectable and oral solutions. Thus, those skilled in the art will be familiar with methods for testing the stability of metoclopramide compositions. Color standards include those listed in 32 USP <631> In some embodiments, another color standard that may be useful for determining the stability of intranasal metoclopramide solutions is a 50:50 dilution of standard C with distilled water, where C is a standard according to 32 USP <631> , as described in 32 USP. A 50:50 dilution of C with distilled water, also referred to herein as 0.5C, can be prepared by creating standard C by combining 1 mL of cobalt chloride CS, 6 mL of ferric chloride CS, 1 mL of copper sulfate CS, and distilled water to 50 mL, and then diluting C to 0.5C by combining 1 part C with 1 part distilled water. Solutions weaker than 0.5C are considered nearly clear as that term is used herein. Cobalt chloride CS, ferric chloride CS, and copper sulfate CS are commercially available colorimetric solutions, but they may also be prepared according to "Colorimetric Solutions (CS)" in the "Reagents, Indicators, and Solutions" section of USP 32, which is incorporated herein by reference in its entirety. In some other preferred embodiments, the color reference standard is prepared according to 32 USP. <631> Standard Matching Solution "E" is prepared by combining 4.0 mL of Cobalt Chloride Colorimetric Solution (USP CS), 12.0 mL of Ferric Chloride Colorimetric Solution (USP CS), and 3.0 mL of Copper Sulfate Solution (USP CS) in a 50 mL volumetric flask and bringing the flask contents to 50 mL with deionized water.Color determination is performed by pipetting 5.0 mL of the standard matching solution into a 20 mL scintillation vial (approximately 15 mm high) and 5.0 mL of the sample solution into another 20 mL scintillation vial (approximately 15 mm high) and comparing the color of the two solutions in diffuse sunlight against a vertical white background. In some embodiments, samples that are clear, lighter in color than the standard, or the same color as the standard are considered "nearly colorless," "nearly clear," or "stable" as described herein. Objectivity can be ensured by having multiple people evaluate the color of the test solution against the standard solution.

[0097] In some embodiments, the metoclopramide compositions described herein are colorless when maintained colorless at a temperature in the range of about 5° C. to about 25° C. for a period of at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, about 9 months, at least about 12 months, at least about 15 months, at least about 18 months, at least about 21 months, or at least about 24 months after formulation. In some embodiments, long-term stability at 5° C. to 25° C. can be simulated under accelerated conditions, e.g., at a temperature in the range of about 35° C. to about 60° C., particularly in the range of about 35° C. to about 45° C., e.g., about 40° C. Thus, in some embodiments, the metoclopramide nasal compositions provided herein are colorless if, after formulation, they remain colorless when stored under accelerated conditions, e.g., at about 25°C to about 60°C, particularly at about 30°C to about 50°C, about 35°C to about 45°C, or about 40°C, for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 9 weeks, at least about 12 weeks, at least about 15 weeks, at least about 18 weeks, at least about 21 weeks, or at least about 24 weeks.

[0098] In some embodiments, compositions comprising metoclopramide or a pharmaceutically acceptable salt thereof exhibit a mean percent change in optical density (OD) of less than about 2% per week of 200 mg / mL of metoclopramide when stored at a temperature of 40° C. and a relative humidity of 75%. In some cases, the mean percent change in optical density (OD) is less than about 1.8% OD per week.

[0099] In some embodiments, the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof has a shelf life of at least about 8 weeks at a temperature of about 40° C. <631> It is a nasal solution that remains clear to pale yellow when compared to standard E.

[0100] buffer In a different embodiment, the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof further comprises a buffering agent, such as citrate / phosphate, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleate, McIlvaine, phosphate, Prideaux-Ward, succinate, citrate-phosphate-borate (Teorell-Stanhagen), valonal acetate, IVIES (2-(N-morpholino)ethanesulfonic acid), BIS-TRIS (bis(2-hydroxyethyl)iminotris(hydroxymethyl)methane), ADA ( N-(2-acetamido)-2-iminodiacetic acid), ACES (N-(carbamoylmethyl)-2-aminoethanesulfonic acid), PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid)), MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid), BIS-TRIS propane (1,3-bis(tris(hydroxymethyl)methylamino)propane), BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid), MOPS (3-(N-morpholino)-2-hydroxypropanesulfonic acid) N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid), TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES (N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid)), DIPSO (3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropanesulfonic acid), MOBS (4-(N-morpholino)butanesulfonic acid), TAPSO (3-(N-tris(hydroxymethyl)methylamino)-2-hydroxypropanesulfonic acid), Tris(N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), (hydroxymethyl)aminomethane, HEPPSO (N-(2-hydroxyethyl)piperazine-N'-(2-hydroxypropanesulfonic acid)), POPSO (piperazine-N,N'-bis(2-hydroxypropanesulfonic acid)), TEA (triethanolamine), EPPS (N-(2-hydroxyethyl)piperazine-N'-(3-propanesulfonic acid)), TWINE (N-tris(hydroxymethyl)methylglycine), GLY-GLY (glycylglycine), BICINE (N,N-bis(2-hydroxyethyl)glycine), HEPBS (N-(2-hydroxyethyl)piperazine-N'-(4-butanesulfonic acid)), TAPS (N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid), and AMPD (2-amino-2-methyl-1,3-propanediol) buffers.

[0101] In embodiments, the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof has a pH greater than about 4.5, e.g., the composition has a pH greater than about 4.6, or the composition has a pH greater than about 5.0.

[0102] In some embodiments, the buffer comprises a citrate buffer. The citrate buffer may comprise a combination of citric acid monohydrate and sodium citrate dihydrate. In some cases, the citric acid monohydrate is present in an amount of about 0.2% to about 0.5% w / v, about 0.25% to about 0.4% w / v, or about 0.3% to about 0.35% w / v, and the sodium citrate dihydrate is present in an amount of about 1.0% to about 1.8% w / v, about 1.2% to about 1.6% w / v, or about 1.3% to about 1.5% w / v. The combined amount of citric acid monohydrate and sodium citrate dihydrate in the composition may be less than about 2.3% w / v. In various cases, the citric acid monohydrate is present in an amount of about 0.1% and the sodium citrate dihydrate is present in an amount of about 0.44%. In some cases, the composition provides a citrate concentration of at least about 10 millimolar.

[0103] In some cases, the buffer comprises sodium acetate.

[0104] In some embodiments, the pH of the nasal metoclopramide formulation should be at least about 4.5, at least about 4.6, at least about 4.7, at least about 4.8, at least about 4.9, at least about 5, at least about 5.1, or at least about 5.2. Achieving and maintaining the appropriate pH may require the use of a buffer. Generally, a buffer comprises a combination of an acid (sometimes abbreviated as HA) and a complementary base (A-). Buffers are sometimes named by describing the acid or base that forms one half of a complementary acid-base (HA-A) pair. For example, acetic acid has the formula CH3C(O)OH and forms a buffer solution in aqueous solution with its complementary base, acetate ion CH3C(O)O-. Buffers formulated in this way are sometimes called acetate buffers or acetate buffers. Those skilled in the art will recognize that the term buffer, when used with either an acid or its complementary base, refers to a mixture of the acid and free base in solution. Thus, a citrate buffer (or citrate buffer) refers to a mixture of citric acid and citrate ions. Because citric acid has three titratable groups, a citrate buffer (or citrate buffer) can refer to a mixture of citric acid and one or more of the complementary bases obtained by removal of one, two, or three protons.

[0105] In some embodiments described herein, it is desirable to combine citric acid monohydrate and sodium citrate dihydrate in a nasal formulation in a ratio suitable to provide a stable pH (±0.2 pH units) of about 4.5 or greater, about 4.6 or greater, about 4.7 or greater, about 4.8 or greater, about 4.9 or greater, about 5 or greater, about 5.1 or greater, about 5.2 or greater, about 5.3 or greater, about 4.5 to about 6.0, about 4.6 to about 5.8, about 4.7 to about 5.6, about 4.5 to about 5.5, about 4.6 to about 5.7, about 4.7 to about 5.8, about 5 to about 5.7, or about 5.1 to about 5.6. It should be understood that the pH of the solution may change slightly upon storage, e.g., under accelerated or ambient conditions. Variations of ±0.05 to ±0.4 pH units, ±0.1 to ±0.3 pH units, or ±0.05 to ±0.25 pH units may be observed upon storage.

[0106] In some embodiments provided herein, it is desirable to combine glacial acetic acid and sodium acetate trihydrate in a nasal formulation in a ratio suitable to provide a stable pH (±0.2 pH units) of about 4.5 or greater, about 4.6 or greater, about 4.7 or greater, about 4.8 or greater, about 4.9 or greater, about 5 or greater, about 5.1 or greater, about 5.2 or greater, about 5.3 or greater, about 4.5 to about 6.0, about 4.6 to about 5.8, about 4.7 to about 5.6, about 4.5 to about 5.5, about 4.6 to about 5.7, about 4.7 to about 5.8, about 5 to about 5.7, or about 5.1 to about 5.6. Variations of ±0.05 to ±0.4 pH units, ±0.1 to ±0.3 pH units, or ±0.05 to ±0.25 pH units may be observed during storage.

[0107] In some embodiments, a suitable buffer has at least one pKa in the range of about 4.2 to about 5.5, about 4.3 to about 5.3, about 4.4 to about 5.2, about 4.5 to about 5.1, or about 4.6 to about 5.0. In some embodiments, a particularly desirable buffer has a pKa in the range of about 4.7 to 4.8. In this regard, it should be noted that acetic acid has a pKa of 4.75, and citric acid has three titratable groups with pKa values ​​of 3.13, 4.76, and 6.40, of which 4.76 is within the range that may be desirable for preparing compositions herein. In some embodiments, other buffers may also be used if they have the appropriate pKa and buffering capacity.

[0108] Buffers used in formulations of the present invention should have sufficient buffering capacity to maintain the pH of the solution within a predetermined range during storage. The buffering capacity of an acid / base buffer system is affected by various factors, particularly the total buffer concentration, which is the combined concentration of the protonated (acid) form of the buffer and each complementary base. For citrate buffers, the total buffer concentration should be at least about 30 mM, or at least about 45 mM, or at least about 55 mM. For acetate buffers, the combined concentration of acetic acid and free acetate ions should be greater than about 70 mM, greater than about 80 mM, or greater than about 90 mM. In some embodiments, the buffering capacity of the selected buffer should be sufficient to maintain the pH within about ±0.1, 0.2, or 0.3 pH units during storage at 25°C to about 45°C for 2, 4, 6, 8, 10, 12, 16, 20, 24 weeks, or longer.

[0109] antioxidants In some embodiments, the nasal metoclopramide compositions can include one or more antioxidants suitable for administration to the nose or nasal cavity. In some embodiments, such antioxidants include citric acid, citric acid monohydrate, sodium citrate dihydrate, butylhydroxyanisole, or a combination of two or more thereof. In some specific embodiments, the antioxidant can include citric acid, citric acid monohydrate, and / or sodium citrate dihydrate. Thus, citric acid, citric acid monohydrate, and / or sodium citrate dihydrate can function as both a buffering agent and an antioxidant.

[0110] In various embodiments, the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof is substantially free of additional antioxidants.

[0111] As used herein, "substantially free of any additional antioxidants" means that the solution does not contain any additional antioxidants other than those explicitly listed. In some embodiments, the solution may contain citrate as defined herein and is substantially free of any additional antioxidants.

[0112] As used herein, particularly with respect to citric acid, "as an antioxidant" means that the component is added for the purpose of imparting antioxidant value to the solution, and not a conjugate salt of that component (e.g., citric acid) or other pH adjuster (e.g., sodium hydroxide) for the purpose of bringing the solution to a particular pH. Thus, the use of a component "as an oxidizing agent" is distinguished from the use of the same component as a buffer, where a particular pH or pH range is achieved by adding a particular amount of acid and conjugate salt or base. This reflects the inventors' discovery that, in some embodiments, the addition of an acidic component, such as citric acid, to a solution stabilizes metoclopramide and protects the solution from discoloration, and that, in some embodiments, there is no need to counteract the acidity of such an acidic component with a conjugate salt or to form a conjugate salt in situ by adding a base to achieve this stability and tendency to resist discoloration.

[0113] Certain excipients In some embodiments, nasal metoclopramide compositions can include one or more specific excipients suitable for nasal or intranasal administration. In some embodiments, such excipients include citric acid, sodium citrate, benzalkonium chloride, sorbitol, sugar, edetate disodium dihydrate (EDTA), or a combination of two or more thereof. In some specific embodiments, the excipient can include citric acid and / or sodium citrate dihydrate. In some embodiments, the excipient can include benzalkonium chloride, or a combination of benzalkonium chloride and citric acid and / or sodium citrate. In some embodiments, the excipient can include a combination of benzalkonium chloride and sorbitol, optionally with one or both of citric acid and sodium citrate.

[0114] In some embodiments, the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof further comprises at least one member of the group consisting of a salt, edetate disodium dihydrate (EDTA), sorbitol, a sugar, and a flavoring agent.

[0115] definition Unless otherwise defined, all technical terms, notations, and other technical and scientific terms used herein shall have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. In some cases, terms having a commonly understood meaning are defined herein for purposes of clarity and / or ease of reference, but the recitation of such definitions herein should not necessarily be construed as representing a substantial difference from what is commonly understood in the art.

[0116] As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Furthermore, wherever the words "including," "includes," "having," "has," "with," or variations thereof are used in either the detailed description and / or claims, such terms are intended to be as inclusive as the term "comprising."

[0117] The term "about" or "approximately" means within an acceptable error range for a particular value, as determined by one of ordinary skill in the art, and depends in part on the method of measuring or determining the value, i.e., the limitations of the measurement system. For example, "about" can mean within one standard deviation, or more than one standard deviation, as practiced in the art. Alternatively, "about" can mean a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a particular value. In some cases, the term "about" refers to ±10% of a stated number or value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold of a value. Unless otherwise specified, when a particular value is described in this application and claims, the term "about" should be assumed to mean within an acceptable error range for the particular value.

[0118] As used herein, the terms "at least one," "one or more," and "and / or" are open-ended and have both conjunctive and disjunctive effects. For example, "at least one of A, B, and C," "at least one of A, B, or C," "one or more of A, B, and C," and "A, B, and / or C" mean A only, B only, C only, A and B, A and C, B and C, or A, B, and C.

[0119] As used herein, "or" can refer to "and," "or," or "and / or," and can be used in both exclusive and inclusive terms. For example, the term "A or B" can refer to "A or B," "A but not B," "B but not A," and "A and B." In some cases, the context may dictate a specific meaning.

[0120] The terms "identifying," "measuring," "evaluating," "assessing," "assaying," and "analyzing" are often used interchangeably herein to refer to forms of measurement. These terms include identifying whether an element is present (e.g., detecting). These terms can include quantitative, qualitative, or quantitative and qualitative identification. Evaluating can be relative or absolute. "Detecting the presence of" can include determining the amount present in addition to determining whether it is present, depending on the context.

[0121] The terms "increased," "increasing," or "increase" are used herein to generally mean an increase by a statistically significant amount. In some embodiments, the term "increased" or "increase" refers to an increase of at least 10% compared to a reference level, e.g., an increase of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% compared to a reference level, standard, or control, or an increase of up to and including 100%, or any increase between 10 and 100%. Other examples of "increase" include an increase of at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 1000-fold, or more compared to a reference level.

[0122] The terms "decreased," "decreasing," or "reduction" are used herein to generally refer to a statistically significant decrease. In some embodiments, "decreased" or "reduction" refers to a decrease of at least 10% compared to a reference level, e.g., at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or up to and including a 100% decrease compared to a reference level (e.g., an absent or undetectable level compared to a reference level), or any decrease between 10% and 100%. In the context of a marker or symptom, these terms refer to a statistically significant decrease in such level. This decrease can be, for example, at least 10%, at least 20%, at least 30%, at least 40%, or more, preferably to a level considered within the normal range in individuals without the particular disease.

[0123] The terms "subject," "individual," or "patient" are often used interchangeably herein. A "subject" can be a biological entity that contains expressed genetic material. The biological entity can be, for example, a plant, animal, or microorganism, including bacteria, viruses, fungi, and protozoa. The subject can be tissues, cells, and their progeny of a biological entity obtained in vivo or cultured in vitro. The subject can be a mammal. The mammal can be a human. The subject can have been diagnosed or be suspected of being at increased risk for developing a disease. In some cases, the subject has not necessarily been diagnosed or is suspected of being at increased risk for the disease.

[0124] As used herein, the terms "treatment" or "treating" refer to a pharmaceutical or other intervention regimen intended to achieve a beneficial or desired result in a recipient. Beneficial or desired results include, but are not limited to, a therapeutic effect and / or a prophylactic effect. A therapeutic effect may refer to the eradication or amelioration of the symptom or underlying disease being treated. A therapeutic effect may also result from the eradication or amelioration of one or more physiological symptoms associated with the underlying disease, and some improvement may be observed in a subject even if the subject still has the underlying disease. A prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. For the purpose of a prophylactic effect, treatment can be administered to subjects at risk of developing a particular disease or who report one or more physiological symptoms of a disease, even if the disease has not been diagnosed.

[0125] The term "therapeutically effective amount" or "effective amount" refers to the amount of a compound or composition that, when administered, is sufficient to prevent the onset of, or alleviate to some extent, one or more symptoms of, the disorder, disease, or condition being treated. The term "therapeutically effective amount" or "effective amount" also refers to the amount of a compound or composition that is sufficient to obtain the biological or medical response in a cell, tissue, system, animal, or human that is desired by a researcher, veterinarian, physician, or clinician.

[0126] The terms "nasal metoclopramide", "intranasal composition comprising metoclopramide", "nasal solution", "nasal metoclopramide formulation", "nasally administered metoclopramide", "intranasal administration" or "intranasal" refer to compounds, compositions, formulations and the like that are intended for administration into the nose (e.g., through the nostrils).

[0127] As used herein, "oral" means a dosage form taken orally, such as a tablet, powder, soft gel capsule, hard gel capsule, orally dissolving tablet or thin film, or liquid.

[0128] Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the present disclosure. Accordingly, the description of a range should be considered to specifically disclose all possible subranges and individual numerical values ​​within that range. For example, the description of a range such as 1 to 6 should be considered to specifically disclose subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, and 3 to 6, as well as individual numerical values ​​within that range, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0129] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. [Example]

[0130] Example 1 This example discloses a method for treating chronic gastroparesis in a patient in need thereof, comprising the steps of intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a first period of time, not administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a second period of time after the first period of time, and intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a third period of time after the second period of time.

[0131] The composition comprising metoclopramide can be any of the compositions disclosed herein comprising metoclopramide.

[0132] Optionally, the method may include a fourth, fifth, sixth, or seventh period similar to the first or second period described above.

[0133] These periods are as described elsewhere herein.

[0134] In this example, the patient does not experience tardive dyskinesia symptoms during the implementation of the method.

[0135] In this example, the patient experiences no symptoms of adverse reactions during the method, including one or more of extrapyramidal effects, neuroleptic malignant syndrome, depression, hypertension, fluid retention, hyperprolactinemia, and inability to drive or operate machinery.

[0136] In this example, the patient is a human, e.g., a female human. The patient, e.g., a female patient, can have diabetic gastroparesis.

[0137] In this example, the patient in need of treatment has symptoms of nausea, bloating, vomiting, delayed vomiting, early satiety, vomiting and diarrhea, satiety, loss of appetite, stomach bloating, visibly large stomach, and upper abdominal discomfort, in some cases, the symptoms associated with diabetic gastroparesis.

[0138] In this example, the decrease in likelihood or probability is at least a 10% decrease in likelihood or probability, at least a 20% decrease in likelihood or probability, at least a 30% decrease in likelihood or probability, at least a 40% decrease in likelihood or probability, at least a 50% decrease in likelihood or probability, at least a 60% decrease in likelihood or probability, at least a 70% decrease in likelihood or probability, at least an 80% decrease in likelihood or probability, or at least a 90% decrease in likelihood or probability. In some cases, the decrease in likelihood or probability is at least a 1-fold decrease in likelihood or probability, at least a 2-fold decrease in likelihood or probability, at least a 3-fold decrease in likelihood or probability, at least a 4-fold decrease in likelihood or probability, at least a 5-fold decrease in likelihood or probability, at least a 6-fold decrease in likelihood or probability, at least a 7-fold decrease in likelihood or probability, at least an 8-fold decrease in likelihood or probability, at least a 9-fold decrease in likelihood or probability, or at least a 10-fold decrease in likelihood or probability.

[0139] Example 2. This example is a method for treating recurrent gastroparesis in a patient in need thereof. The method includes intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof. The patient has previously been administered a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof intranasally for a first period of time, and the patient has not been administered a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof intranasally for a second period of time after the first period of time.

[0140] The composition comprising metoclopramide can be any of the compositions disclosed herein comprising metoclopramide.

[0141] Optionally, the method may include a fourth, fifth, sixth, or seventh period similar to the first or second period described above.

[0142] These periods are as described elsewhere herein.

[0143] In this example, the patient does not experience tardive dyskinesia symptoms during the implementation of the method.

[0144] In this example, the patient experiences no symptoms of adverse reactions during the method, including one or more of extrapyramidal effects, neuroleptic malignant syndrome, depression, hypertension, fluid retention, hyperprolactinemia, and inability to drive or operate machinery.

[0145] In this example, the patient is a human, e.g., a female human. The patient, e.g., a female patient, can have diabetic gastroparesis.

[0146] In this example, the patient in need of treatment has symptoms of nausea, bloating, vomiting, delayed vomiting, early satiety, vomiting and diarrhea, satiety, loss of appetite, stomach bloating, visibly large stomach, and upper abdominal discomfort, in some cases, the symptoms associated with diabetic gastroparesis.

[0147] In this example, the decrease in likelihood or probability is at least a 10% decrease in likelihood or probability, at least a 20% decrease in likelihood or probability, at least a 30% decrease in likelihood or probability, at least a 40% decrease in likelihood or probability, at least a 50% decrease in likelihood or probability, at least a 60% decrease in likelihood or probability, at least a 70% decrease in likelihood or probability, at least an 80% decrease in likelihood or probability, or at least a 90% decrease in likelihood or probability. In some cases, the decrease in likelihood or probability is at least a 1-fold decrease in likelihood or probability, at least a 2-fold decrease in likelihood or probability, at least a 3-fold decrease in likelihood or probability, at least a 4-fold decrease in likelihood or probability, at least a 5-fold decrease in likelihood or probability, at least a 6-fold decrease in likelihood or probability, at least a 7-fold decrease in likelihood or probability, at least an 8-fold decrease in likelihood or probability, at least a 9-fold decrease in likelihood or probability, or at least a 10-fold decrease in likelihood or probability.

[0148] Example 3. This example discloses a method for reducing the likelihood or probability that a patient will experience tardive dyskinesia due to metoclopramide therapy. The method includes intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a first period of time, not administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a second period of time after the first period of time, and intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a third period of time after the second period of time.

[0149] The composition comprising metoclopramide can be any of the compositions disclosed herein comprising metoclopramide.

[0150] Optionally, the method may include a fourth, fifth, sixth, or seventh period similar to the first or second period described above.

[0151] These periods are as described elsewhere herein.

[0152] In this example, the patient does not experience tardive dyskinesia symptoms during the implementation of the method.

[0153] In this example, the patient experiences no symptoms of adverse reactions during the method, including one or more of extrapyramidal effects, neuroleptic malignant syndrome, depression, hypertension, fluid retention, hyperprolactinemia, and inability to drive or operate machinery.

[0154] In this example, the patient is a human, e.g., a female human. The patient, e.g., a female patient, can have diabetic gastroparesis.

[0155] In this example, the patient in need of treatment has symptoms of nausea, bloating, vomiting, delayed vomiting, early satiety, vomiting and diarrhea, satiety, loss of appetite, stomach bloating, visibly large stomach, and upper abdominal discomfort, in some cases, the symptoms associated with diabetic gastroparesis.

[0156] In this example, the decrease in likelihood or probability is at least a 10% decrease in likelihood or probability, at least a 20% decrease in likelihood or probability, at least a 30% decrease in likelihood or probability, at least a 40% decrease in likelihood or probability, at least a 50% decrease in likelihood or probability, at least a 60% decrease in likelihood or probability, at least a 70% decrease in likelihood or probability, at least an 80% decrease in likelihood or probability, or at least a 90% decrease in likelihood or probability. In some cases, the decrease in likelihood or probability is at least a 1-fold decrease in likelihood or probability, at least a 2-fold decrease in likelihood or probability, at least a 3-fold decrease in likelihood or probability, at least a 4-fold decrease in likelihood or probability, at least a 5-fold decrease in likelihood or probability, at least a 6-fold decrease in likelihood or probability, at least a 7-fold decrease in likelihood or probability, at least an 8-fold decrease in likelihood or probability, at least a 9-fold decrease in likelihood or probability, or at least a 10-fold decrease in likelihood or probability.

[0157] Example 4. This example discloses a method for reducing the likelihood or probability that a patient will experience tardive dyskinesia due to metoclopramide therapy. The method includes intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof. The patient has previously been intranasally administered a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a first period of time, and the patient has not been intranasally administered a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a second period of time following the first period of time.

[0158] The composition comprising metoclopramide can be any of the compositions disclosed herein comprising metoclopramide.

[0159] Optionally, the method may include a fourth, fifth, sixth, or seventh period similar to the first or second period described above.

[0160] These periods are as described elsewhere herein.

[0161] In this example, the patient does not experience tardive dyskinesia symptoms during the implementation of the method.

[0162] In this example, the patient experiences no symptoms of adverse reactions during the method, including one or more of extrapyramidal effects, neuroleptic malignant syndrome, depression, hypertension, fluid retention, hyperprolactinemia, and inability to drive or operate machinery.

[0163] In this example, the patient is a human, e.g., a female human. The patient, e.g., a female patient, can have diabetic gastroparesis.

[0164] In this example, the patient in need of treatment has symptoms of nausea, bloating, vomiting, delayed vomiting, early satiety, vomiting and diarrhea, satiety, loss of appetite, stomach bloating, visibly large stomach, and upper abdominal discomfort, in some cases, the symptoms associated with diabetic gastroparesis.

[0165] In this example, the decrease in likelihood or probability is at least a 10% decrease in likelihood or probability, at least a 20% decrease in likelihood or probability, at least a 30% decrease in likelihood or probability, at least a 40% decrease in likelihood or probability, at least a 50% decrease in likelihood or probability, at least a 60% decrease in likelihood or probability, at least a 70% decrease in likelihood or probability, at least an 80% decrease in likelihood or probability, or at least a 90% decrease in likelihood or probability. In some cases, the decrease in likelihood or probability is at least a 1-fold decrease in likelihood or probability, at least a 2-fold decrease in likelihood or probability, at least a 3-fold decrease in likelihood or probability, at least a 4-fold decrease in likelihood or probability, at least a 5-fold decrease in likelihood or probability, at least a 6-fold decrease in likelihood or probability, at least a 7-fold decrease in likelihood or probability, at least an 8-fold decrease in likelihood or probability, at least a 9-fold decrease in likelihood or probability, or at least a 10-fold decrease in likelihood or probability.

[0166] Example 5. This example discloses a method for reducing the likelihood or probability that a patient will experience an adverse reaction due to metoclopramide therapy. The method includes intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a first period of time; after the first period of time, not administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a second period of time; and after the second period of time, intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a third period of time. In this case, the adverse reaction is one or more of extrapyramidal effects, neuroleptic malignant syndrome, depression, hypertension, fluid retention, hyperprolactinemia, and inability to drive or operate machinery.

[0167] The composition comprising metoclopramide can be any of the compositions disclosed herein comprising metoclopramide.

[0168] Optionally, the method may include a fourth, fifth, sixth, or seventh period similar to the first or second period described above.

[0169] These periods are as described elsewhere herein.

[0170] In this example, the patient does not experience tardive dyskinesia symptoms during the implementation of the method.

[0171] In this example, the patient experiences no symptoms of adverse reactions during the method, including one or more of extrapyramidal effects, neuroleptic malignant syndrome, depression, hypertension, fluid retention, hyperprolactinemia, and inability to drive or operate machinery.

[0172] In this example, the patient is a human, e.g., a female human. The patient, e.g., a female patient, can have diabetic gastroparesis.

[0173] In this example, the patient in need of treatment has symptoms of nausea, bloating, vomiting, delayed vomiting, early satiety, vomiting and diarrhea, satiety, loss of appetite, stomach bloating, visibly large stomach, and upper abdominal discomfort, in some cases, the symptoms associated with diabetic gastroparesis.

[0174] In this example, the decrease in likelihood or probability is at least a 10% decrease in likelihood or probability, at least a 20% decrease in likelihood or probability, at least a 30% decrease in likelihood or probability, at least a 40% decrease in likelihood or probability, at least a 50% decrease in likelihood or probability, at least a 60% decrease in likelihood or probability, at least a 70% decrease in likelihood or probability, at least an 80% decrease in likelihood or probability, or at least a 90% decrease in likelihood or probability. In some cases, the decrease in likelihood or probability is at least a 1-fold decrease in likelihood or probability, at least a 2-fold decrease in likelihood or probability, at least a 3-fold decrease in likelihood or probability, at least a 4-fold decrease in likelihood or probability, at least a 5-fold decrease in likelihood or probability, at least a 6-fold decrease in likelihood or probability, at least a 7-fold decrease in likelihood or probability, at least an 8-fold decrease in likelihood or probability, at least a 9-fold decrease in likelihood or probability, or at least a 10-fold decrease in likelihood or probability.

[0175] Example 6 This example discloses a method for reducing the likelihood or probability that a patient will experience an adverse reaction due to metoclopramide therapy. The method includes intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof. The patient has previously been administered a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof intranasally for a first period of time. The patient has not been administered a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof intranasally for a second period of time after the first period of time. The adverse reaction is one or more of extrapyramidal effects, neuroleptic malignant syndrome, depression, hypertension, fluid retention, hyperprolactinemia, and inability to drive or operate machinery.

[0176] The composition comprising metoclopramide can be any of the compositions disclosed herein comprising metoclopramide.

[0177] Optionally, the method may include a fourth, fifth, sixth, or seventh period similar to the first or second period described above.

[0178] These periods are as described elsewhere herein.

[0179] In this example, the patient does not experience tardive dyskinesia symptoms during the implementation of the method.

[0180] In this example, the patient experiences no symptoms of adverse reactions during the method, including one or more of extrapyramidal effects, neuroleptic malignant syndrome, depression, hypertension, fluid retention, hyperprolactinemia, and inability to drive or operate machinery.

[0181] In this example, the patient is a human, e.g., a female human. The patient, e.g., a female patient, can have diabetic gastroparesis.

[0182] In this example, the patient in need of treatment has symptoms of nausea, bloating, vomiting, delayed vomiting, early satiety, vomiting and diarrhea, satiety, loss of appetite, stomach bloating, visibly large stomach, and upper abdominal discomfort, in some cases, the symptoms associated with diabetic gastroparesis.

[0183] In this example, the decrease in likelihood or probability is at least a 10% decrease in likelihood or probability, at least a 20% decrease in likelihood or probability, at least a 30% decrease in likelihood or probability, at least a 40% decrease in likelihood or probability, at least a 50% decrease in likelihood or probability, at least a 60% decrease in likelihood or probability, at least a 70% decrease in likelihood or probability, at least an 80% decrease in likelihood or probability, or at least a 90% decrease in likelihood or probability. In some cases, the decrease in likelihood or probability is at least a 1-fold decrease in likelihood or probability, at least a 2-fold decrease in likelihood or probability, at least a 3-fold decrease in likelihood or probability, at least a 4-fold decrease in likelihood or probability, at least a 5-fold decrease in likelihood or probability, at least a 6-fold decrease in likelihood or probability, at least a 7-fold decrease in likelihood or probability, at least an 8-fold decrease in likelihood or probability, at least a 9-fold decrease in likelihood or probability, or at least a 10-fold decrease in likelihood or probability.

[0184] Incorporation by Reference All publications, patents, and patent applications mentioned herein are hereby incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. Specifically, US 6,770,262; US 8,334,281; US ​​11,020,361; US ​​11,517,545; US 2013 / 0217775; US 2020 / 0276139; and US 2022 / 0151960 are hereby incorporated by reference in their entireties. To the extent that the publications and patents or patent applications incorporated by reference conflict with the disclosure contained herein, the present specification shall supersede and / or supersede any such conflicting material.

Claims

1. 1. A method for treating chronic gastroparesis in a patient in need thereof, comprising: intranasally administering to said patient for a first period of time a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof; administering to said patient for a second period of time subsequent to said first period of time no composition comprising metoclopramide or a pharmaceutically acceptable salt thereof; and intranasally administering to said patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a third period of time following said second period of time.

2. 1. A method of treating recurrent gastroparesis in a patient in need thereof, comprising intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof; the patient has previously been administered intranasally a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a first period of time; The method, wherein the patient has not been administered intranasally a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a second period of time following the first period of time.

3. 1. A method for reducing the likelihood or probability that a patient will experience tardive dyskinesia due to metoclopramide therapy, comprising: intranasally administering to said patient for a first period of time a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof; administering to said patient for a second period of time subsequent to said first period of time no composition comprising metoclopramide or a pharmaceutically acceptable salt thereof; and intranasally administering to said patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a third period of time following said second period of time.

4. 1. A method for reducing the likelihood or probability that a patient will experience tardive dyskinesia due to metoclopramide therapy, comprising the step of intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof; the patient has previously been administered intranasally a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a first period of time; The method, wherein the patient has not been administered intranasally a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a second period of time following the first period of time.

5. 1. A method for reducing the likelihood or probability that a patient will experience an adverse reaction due to metoclopramide therapy, comprising: intranasally administering to said patient for a first period of time a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof; administering to said patient for a second period of time subsequent to said first period of time no composition comprising metoclopramide or a pharmaceutically acceptable salt thereof; and intranasally administering to said patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a third period of time subsequent to said second period of time; The method, wherein the adverse reaction is one or more of extrapyramidal effects, neuroleptic malignant syndrome, depression, hypertension, fluid retention, hyperprolactinemia, and inability to drive or operate machinery.

6. 1. A method for reducing the likelihood or probability that a patient will experience an adverse reaction due to metoclopramide therapy, comprising the step of intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof; the patient has previously been administered intranasally a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a first period of time; the patient has not been intranasally administered a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a second period of time subsequent to the first period of time; The method, wherein the adverse reaction is one or more of extrapyramidal effects, neuroleptic malignant syndrome, depression, hypertension, fluid retention, hyperprolactinemia, and inability to drive or operate machinery.

7. 7. The method of any one of claims 1 to 6, wherein the sum of the first period of time and the third period of time is greater than 12 weeks.

8. 8. The method of any one of claims 1 to 7, wherein the first period of time is longer than 12 weeks and / or the third period of time is longer than 12 weeks.

9. 8. The method of any one of claims 1 to 7, wherein the first period of time is from about 2 weeks to about 8 weeks and / or the third period of time is from about 2 weeks to about 8 weeks.

10. 9. The method of any one of claims 1 to 8, wherein the second period of time is at least 5 days, at least 6 days, or at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 12 days, at least 13 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 2 months, or at least 3 months.

11. 11. The method of any one of claims 1 to 10, further comprising the step of not administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a fourth period of time subsequent to the third period of time.

12. 12. The method of claim 11, further comprising the step of intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a fifth period of time after the fourth period of time.

13. 13. The method of claim 11 or claim 12, wherein the fourth period of time is at least 5 days, at least 6 days, or at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 12 days, at least 13 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 2 months, or at least 3 months.

14. 14. The method of claim 12 or claim 13, wherein the fifth period of time is greater than 12 weeks, or the fifth period of time is from about 2 weeks to about 8 weeks.

15. 15. The method of any one of claims 11 to 14, further comprising the step of not administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a sixth period of time subsequent to the fifth period of time.

16. 16. The method of claim 15, further comprising the step of intranasally administering to the patient a composition comprising metoclopramide or a pharmaceutically acceptable salt thereof for a seventh period of time subsequent to the sixth period of time.

17. 17. The method of claim 15 or claim 16, wherein the sixth period of time is at least 5 days, at least 6 days, or at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 12 days, at least 13 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 2 months, or at least 3 months.

18. 18. The method of claim 16 or claim 17, wherein the seventh period of time is greater than 12 weeks, or the seventh period of time is from about 2 weeks to about 8 weeks.

19. 19. The method of any one of claims 1 to 18, wherein the method is carried out for more than 12 weeks.

20. 20. The method of claim 19, wherein the method is carried out for six months or more.

21. 21. The method of claim 20, wherein the method is carried out for one year or more.

22. 22. The method of claim 21, wherein the method is carried out for two or more years.

23. 23. The method of claim 22, wherein the method is carried out for three or more years.

24. 24. The method of claim 23, wherein the method is carried out for four or more years.

25. 25. The method of claim 24, wherein the method is carried out for five years or more.

26. 26. The method of any one of claims 2 to 25, wherein reducing the likelihood or probability is at least a 10% reduction in likelihood or probability compared to a method lacking at least the second period of time.

27. 27. The method of any one of claims 11 to 26, wherein reducing the likelihood or probability is at least a 10% reduction in likelihood or probability compared to a method lacking at least a fourth period of time.

28. 28. The method of any one of claims 15 to 27, wherein reducing the likelihood or probability is at least a 10% reduction in likelihood or probability compared to a method lacking at least a sixth period of time.

29. 29. The method of any one of claims 26 to 28, wherein reducing the likelihood or probability is at least a 20% reduction in likelihood or probability, at least a 30% reduction in likelihood or probability, at least a 40% reduction in likelihood or probability, at least a 50% reduction in likelihood or probability, at least a 60% reduction in likelihood or probability, at least a 70% reduction in likelihood or probability, at least an 80% reduction in likelihood or probability, or at least a 90% reduction in likelihood or probability.

30. 30. The method of any one of claims 26 to 29, wherein reducing the likelihood or probability is at least a 1-fold decrease in likelihood or probability, at least a 2-fold decrease in likelihood or probability, at least a 3-fold decrease in likelihood or probability, at least a 4-fold decrease in likelihood or probability, at least a 5-fold decrease in likelihood or probability, at least a 6-fold decrease in likelihood or probability, at least a 7-fold decrease in likelihood or probability, at least an 8-fold decrease in likelihood or probability, at least a 9-fold decrease in likelihood or probability, or at least a 10-fold decrease in likelihood or probability.

31. 31. The method of any one of claims 1 to 30, wherein the patient does not experience symptoms of tardive dyskinesia during the administration of the method.

32. the patient does not experience any symptoms of an adverse reaction during the administration of the method; 32. The method of any one of claims 1 to 31, wherein the adverse reaction is one or more of extrapyramidal effects, neuroleptic malignant syndrome, depression, hypertension, fluid retention, hyperprolactinemia, and inability to drive or operate machinery.

33. 33. The method of any one of claims 1 to 32, wherein the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof further comprises benzalkonium chloride.

34. 34. The method of claim 33, wherein the composition has a concentration of benzalkonium chloride of about 0.005% (w / v) to about 0.05% (w / v).

35. 35. The method of claim 34, wherein the benzalkonium chloride is at a concentration of about 0.02% to about 0.04% (w / v).

36. 36. The method of claim 35, wherein the benzalkonium chloride is at a concentration of about 0.02% to about 0.03% (w / v).

37. 37. The method of claim 36, wherein the benzalkonium chloride is at a concentration of at least about 0.025% (w / v).

38. 38. The method of claim 37, wherein the benzalkonium chloride is at a concentration of about 0.025% (w / v).

39. 39. The method of any one of claims 1 to 38, wherein the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof further comprises benzyl alcohol.

40. 40. The method of claim 39, wherein the benzyl alcohol is at a concentration of about 0.01% (w / v) to about 1% (w / v).

41. 41. The method of claim 39 or claim 40, wherein the benzyl alcohol is at a concentration of about 0.75% (w / v).

42. 42. The method of any one of claims 1 to 41, wherein the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof further comprises a buffering agent.

43. The buffer may be selected from the group consisting of citric acid / phosphate, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleic acid, McIlvaine, phosphate, Prideaux-Ward, succinate, citrate-phosphate-borate (Teorell-Stanhagen), valonal acetate, IVIES (2-(N-morpholino)ethanesulfonic acid), BIS-TRIS (bis(2-hydroxyethyl)iminotris(hydroxymethyl)methane), ADA (N-(2-acetamido)-2-iminodiacetic acid), ACES (N-(carbamoylmethyl)-2-aminoethanesulfonic acid), PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid)), MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid), BIS-TRISpropane (1,3-bis(tris(hydroxymethyl)methylamino)propane), BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid), MOPS (3-(N-morpholino)-2-hydroxypropanesulfonic acid), N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid)), TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES (N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid)), DIPSO (3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropanesulfonic acid), MOBS (4-(N-morpholino)butanesulfonic acid), TAPSO (3-(N-tris(hydroxymethyl)methylamino)-2-hydroxypropanesulfonic acid), Tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), Bis(hydroxymethyl)aminomethane, HEPPSO (N-(2-hydroxyethyl)piperazine-N'-(2-hydroxypropanesulfonic acid)), POPSO (piperazine-N,N'-bis(2-hydroxypropanesulfonic acid)), TEA (triethanolamine), EPPS (N-(2-hydroxyethyl)piperazine-N'-(3-propanesulfonic acid)), TWINE (N-tris(hydroxymethyl)methylglycine), GLY-GLY (glycylglycine), BICINE (N,43. The method of claim 42, wherein the buffer is selected from the group consisting of N-bis(2-hydroxyethyl)glycine), HEPBS (N-(2-hydroxyethyl)piperazine-N'-(4-butanesulfonic acid)), TAPS (N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid), and AMPD (2-amino-2-methyl-1,3-propanediol).

44. 44. The method of claim 42 or claim 43, wherein the buffer comprises a citrate buffer.

45. 45. The method of claim 44, wherein the citrate buffer comprises a combination of citric acid monohydrate and sodium citrate dihydrate.

46. 46. ​​The method of claim 45, wherein the citric acid monohydrate is in an amount of about 0.2% to about 0.5% w / v, about 0.25% to about 0.4% w / v, or about 0.3% to about 0.35% w / v, and the sodium citrate dihydrate is in an amount of about 1.0 to about 1.8% w / v, about 1.2 to about 1.6% w / v, or about 1.3 to about 1.5% w / v.

47. 47. The method of claim 45 or claim 46, wherein the total amount of citric acid monohydrate and sodium citrate dihydrate in the composition is less than about 2.3% w / v.

48. 48. The method of any one of claims 45 to 47, wherein the citric acid monohydrate is in an amount of about 0.1% and the sodium citrate dihydrate is in an amount of about 0.44%.

49. 49. The method of any one of claims 45 to 48, wherein the composition provides a citrate concentration of at least about 10 millimolar.

50. 50. The method of any one of claims 42 to 49, wherein the buffer comprises sodium acetate.

51. 51. The method of any one of claims 1 to 50, wherein the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof has a pH greater than about 4.

5.

52. 52. The method of claim 51, wherein the composition has a pH greater than about 4.

6.

53. 53. The method of claim 52, wherein the composition has a pH greater than about 5.

0.

54. 54. The method of any one of claims 1 to 53, wherein the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof further comprises at least one member of the group consisting of a salt, edetate disodium dihydrate (EDTA), sorbitol, a sugar, and a flavoring agent.

55. 55. The method of any one of claims 1 to 54, wherein the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof is substantially free of additional antioxidants.

56. 56. The method of any one of claims 1 to 55, wherein the composition has a concentration of metoclopramide or a pharmaceutically acceptable salt thereof of about 20.0% (w / v) to about 30.0% (w / v).

57. 57. The method of claim 56, wherein the composition comprises 5 mg to 25 mg of metoclopramide or a pharmaceutically acceptable salt thereof per aliquot.

58. 58. The method of claim 56 or claim 57, wherein the metoclopramide composition contains about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg of metoclopramide or a pharmaceutically acceptable salt thereof per aliquot.

59. 59. The method of any one of claims 56 to 58, wherein a dose of 20 mg to 100 mg of metoclopramide or a pharmaceutically acceptable salt thereof is administered per day.

60. 60. The method of any one of claims 56 to 59, wherein a dose of 30 mg to 80 mg of metoclopramide or a pharmaceutically acceptable salt thereof is administered per day.

61. 61. The method of any one of claims 56 to 60, wherein a dose of 30 mg to 60 mg of metoclopramide or a pharmaceutically acceptable salt thereof is administered per day.

62. 62. The method of any one of claims 56 to 61, wherein a dose of 30 mg to 45 mg of metoclopramide or a pharmaceutically acceptable salt thereof is administered per day.

63. 63. The method of any one of claims 1 to 62, wherein the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof is administered in at least two aliquots per day.

64. 64. The method of claim 63, wherein the composition is administered in three aliquots per day.

65. 64. The method of claim 63, wherein the composition is administered in four aliquots per day.

66. 63. The method of any one of claims 1 to 62, wherein the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof is administered as an intranasal spray.

67. 67. The method of any one of claims 1 to 66, wherein the aliquot of composition comprising metoclopramide or a pharmaceutically acceptable salt thereof has a volume of about 25 μL to about 140 μL.

68. 68. The method of claim 67, wherein the aliquot of the composition has a volume of about 50 μL.

69. 68. The method of claim 67, wherein the aliquot of the composition has a volume of about 70 μL.

70. 70. The method of any one of claims 1 to 69, wherein the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof is administered as a single spray into one nostril about 15 minutes to about 1 hour before a meal.

71. 71. The method of claim 70, wherein the composition is administered as a single spray into one nostril about 20 minutes to about 45 minutes before a meal.

72. 72. The method of claim 71, wherein the composition is administered as a single spray into one nostril about 30 minutes before a meal.

73. 73. The method of any one of claims 1 to 72, wherein the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof has an osmolality of about 500 mOsm / kg to about 1400 mOsm / kg.

74. 74. The method of any one of claims 1 to 73, wherein the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof comprises benzalkonium chloride, citric acid monohydrate, edetate disodium dihydrate (EDTA), purified water, sodium citrate dihydrate, and sorbitol.

75. 75. The method of claim 74, wherein each 70 μL aliquot of the composition contains 15 mg of metoclopramide or a pharmaceutically acceptable salt thereof, each 70 μL aliquot of the composition contains 7.5 mg of metoclopramide or a pharmaceutically acceptable salt thereof, or each 35 μL aliquot of the composition contains 7.5 mg of metoclopramide.

76. 76. The method of claim 74 or claim 75, wherein the composition has a pH of about 5.

5.

77. 77. The method of any one of claims 74-76, wherein the composition has a citrate concentration ([citrate] = [citric acid] + [dihydrogen citrate ions] + [hydrogen citrate ions] + [citrate ions]) of at least about 10 millimolar.

78. 74. The method of any one of claims 1 to 73, wherein the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof comprises benzyl alcohol, citric acid monohydrate, edetate disodium dihydrate (EDTA), purified water, sodium citrate dihydrate, and sorbitol.

79. 79. The method of claim 78, wherein the composition comprises less than about 1% w / v benzyl alcohol.

80. 74. The method of any one of claims 1 to 73, wherein the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof comprises benzyl alcohol, acetate buffer, edetate disodium dihydrate (EDTA), purified water, and sorbitol.

81. 81. The method of any one of claims 1 to 80, wherein the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof exhibits an average percent change in optical density (OD) of less than about 2% per 200 mg / mL of metoclopramide per week when stored at a temperature of 40°C and a relative humidity of 75%.

82. 82. The method of claim 81, wherein the average percent change in optical density (OD) is less than about 1.8% OD per week.

83. 83. The method of any one of claims 1 to 82, wherein the composition comprising metoclopramide or a pharmaceutically acceptable salt thereof is a nasal solution that maintains a clear to pale yellow color when compared to Standard E of 32 USP <631> upon storage at a temperature of about 40°C for at least about 8 weeks.

84. 84. The method of any one of claims 1-83, wherein the patient in need of said treatment has symptoms of nausea, bloating, vomiting, delayed vomiting, early satiety, diarrhea, fullness, loss of appetite, stomach bloating, visibly large stomach, and upper abdominal discomfort.

85. 85. The method of any one of claims 1 to 84, wherein the patient in need of treatment is a human.

86. 86. The method of claim 85, wherein the human is a female.

87. 87. The method of claim 85 or claim 86, wherein the human is an adult.

88. 88. The method of any one of claims 1 to 87, wherein the patient has diabetic gastroparesis.

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