Preparations containing deuterated domperidone

Abstract

To provide a safe and effective formulation of domperidone. The present invention provides a pharmaceutical formulation comprising deuterated d4-domperidone or a pharmaceutically acceptable salt thereof, the formulation comprising (i) glyceryl stearate and a medium-chain triglyceride, or (ii) a stearoyl polyoxylglyceride, a non-ionic poly(ethylene oxide) polymer, and a medium-chain triglyceride, or (iii) a non-ionic poly(ethylene oxide) polymer and polyethylene glycol.

Description

[Technical field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 750,491, filed October 25, 2018, the contents of which are incorporated herein by reference.

[0002] The present disclosure relates to pharmaceutical formulations containing d4-domperidone. [Background technology]

[0003] Gastroparesis is a condition in which gastric motility does not function or does not function normally, causing the stomach to not empty and impeding digestion. Treatment of gastroparesis requires drugs such as metoclopramide, erythromycin, or cisapride to stimulate the stomach muscles. Metoclopramide has serious side effects, including causing motility disorders and interactions with other drugs, erythromycin may become ineffective as patients develop a tolerance to the drug, and cisapride has limited use.

[0004] Gastroparesis may be treated with medications to suppress nausea and vomiting, such as prochlorperazine, thiethylperazine, diphenhydramine, or ondansetron. Gastroparesis can also be treated surgically, for example by placing a jejunostomy tube, a gastric drainage tube, or a feeding tube.

[0005] Deuterated and non-deuterated domperidone are effective dopamine antagonists that do not readily cross the blood-brain barrier and have the potential to be used in the treatment of gastroparesis. Safe and effective formulations of domperidone are needed. Summary of the Invention [Means for solving the problem]

[0006] In some embodiments, the present disclosure provides d4-domperidone of formula (I): [ka] (I) or a pharma- ceutically acceptable salt thereof; glyceryl stearate; and a medium chain triglyceride.

[0007] In other embodiments, the present disclosure provides d4-domperidone of formula (I): [ka] (I) or a pharma- ceutically acceptable salt thereof; a stearoyl polyoxylglyceride; a non-ionic poly(ethylene oxide) polymer; and a medium chain triglyceride.

[0008] In a further embodiment, the present disclosure provides d4-domperidone of formula (I): [ka] (I) or a pharma- ceutically acceptable salt thereof; a non-ionic poly(ethylene oxide) polymer; and polyethylene glycol.

[0009] In yet another embodiment, the present disclosure provides a method for treating a disorder in a patient that is gastroparesis, nausea other than gastroparesis, vomiting other than gastroparesis, nausea associated with gastroparesis, vomiting associated with gastroparesis, gastroesophageal reflux disease, insufficient lactation, or a combination thereof, comprising administering to the patient a formulation as described herein.In some aspects, the disorder is gastroparesis.In other aspects, the disorder is gastroesophageal reflux disease.In a further aspect, the disorder is insufficient lactation.

[0010] Other aspects and embodiments of the present invention will become readily apparent from the following detailed description of the invention. [Brief description of the drawings]

[0011] This application is better understood when read in conjunction with the accompanying drawings. For the purpose of illustrating the subject matter, the drawings show exemplary embodiments of the subject matter, but the presently disclosed subject matter is not limited to the specific compositions, methods, apparatus, and systems disclosed. Additionally, the drawings are not necessarily drawn to scale.

[0012] [Figure 1] FIG. 1 is a line graph showing the plasma concentrations of d4-domperidone resulting from administration of Formulations A to F. [Diagram 2] FIG. 2 is an enlarged view of FIG. [Diagram 3] FIG. 3 is a line graph showing the mean concentrations of domperidone or d4-domperidone following 1 mg / kg dogs as described in Example 3. [Figure 4] FIG. 4 is an extension of FIG. 3, further showing the Cmax and AUC of domperidone and d4-domperidone in bar graph format. [Diagram 5] FIG. 5 is a line graph comparing plasma levels of d4-domperidone following administration of Formulations A, B, or F to dogs as described in Example 4. [Figure 6] FIG. 6 is a line graph showing the pharmacokinetic profiles of domperidone and d4-domperidone when administered to dogs at a dose of 1 mg / kg. [Figure 7] FIG. 7 is a flow chart of the fill formulation for d4-domperidone placebo and domperidone 5 mg and 10 mg samples. [Figure 8] FIG. 8 is a line graph showing the Cmax and AUC of suspension formulations containing d4-domperidone and domperidone. [Figure 9] FIG. 9 is a line graph showing the corrected absolute QTc values ​​of the d4-domperidone samples of Example 3. [Figure 10] FIG. 10 is a line graph showing the corrected QTc values ​​versus absolute values ​​for non-deuterated domperidone samples of Example 3. [Figure 11]FIG. 11 is a bar graph showing the percent change in Cmax from vehicle for d4-domperidone and non-deuterated domperidone samples of Example 3. [Figure 12] FIG. 12 is a bar graph showing percent Cmax change from vehicle versus dose for d4-domperidone and non-deuterated domperidone samples of Example 3. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] In this disclosure, the singular forms "a," "an," and "the" include plural references, and a reference to a particular value includes at least that particular value unless the context clearly dictates otherwise. Thus, for example, a reference to a "material" is a reference to at least one of such materials and equivalents thereof known to those of skill in the art.

[0014] When a value is expressed as an approximation using the statement "about", it will be understood that the particular value forms another embodiment. In general, the use of the term "about" indicates an approximation that may vary depending on the desired properties sought to be obtained by the disclosed subject matter and should be interpreted in the particular context in which it is used based on its function. One of ordinary skill in the art would be able to interpret this routinely. In some cases, the number of significant figures used for a particular value may be one non-limiting way of determining the scope of the term "about". In other cases, the gradation used for a series of values ​​may be used to determine the intended range available for the term "about" for each value. When present, all ranges are inclusive and combinable; i.e., reference to values ​​stated in a range includes all values ​​within that range.

[0015] When lists are presented, unless otherwise stated, it is to be understood that each individual element of the list and every combination of that list is to be construed as a separate embodiment. For example, a list of embodiments presented as "A, B, or C" is to be construed as including the embodiments "A," "B," "C," "A or B," "A or C," "B or C," or "A, B, or C."

[0016] It is to be understood that certain features of the invention, which are described herein for clarity in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, unless clearly incompatible or excluded, each embodiment is deemed combinable with other embodiment(s), and such combinations are deemed to be separate embodiments. Conversely, various features of the invention, which are described for brevity in the context of a single embodiment, may also be provided separately or in any subcombination. It is further noted that the claims may be drafted to exclude any element. Thus, this specification is intended as a predicate for the use of exclusive language, such as "singlely," "only," or "negative" limitations in connection with the recitation of claim elements. Finally, while an embodiment may be described as part of a series of steps or as part of a more general structure, each said step may also be considered an independent embodiment in itself.

[0017] The terms "subject" and "patient" are used interchangeably and typically refer to a mammal. In some embodiments, the patient or subject is a human. In other embodiments, the patient or subject is a veterinary or farm animal, a livestock or pet, or an animal used to conduct clinical research.

[0018] "Treating" or variations thereof means eliminating or reducing at least one physical parameter of a disease or disorder.

[0019] "Domperidone" as referred to herein means 5-chloro-1-(1-[3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl]piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one, which has the following structure: [ka]

[0020] "D4-domperidone" as referred to herein means 1-{3-[4-(5-chloro-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidin-1yl]propyl}-2,3-dihydro(4,5,6,7-D4)-1H-1,3-benzodiazol-2-one, having the following structure: [ka]

[0021] d4-Domperidone also includes pharma- ceutically acceptable salts, esters, hydrates, solvates, prodrug forms, and derivatives thereof, which are broadly defined as modified or partially substituted d4-Domperidone compounds, including, but not limited to, the addition of a single atom, the addition of a reactive group, the addition of a functional group, the formation of a dimer or multimer, conjugation with another molecule, such as an antibody, and the like.

[0022] "Pharmaceutically acceptable" means properties and / or substances that are pharmacologically / toxicologically acceptable to a patient and physically / chemically acceptable to a pharmaceutical chemist in the manufacturing process, with respect to composition, formulation, stability, patient acceptability, and bioavailability.

[0023] Pharmaceutically acceptable salts include salts with pharma- ceutically acceptable acids or bases, such as inorganic acids, e.g., hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, hydroiodic acid, and nitric acid, and organic acids, such as citric acid, fumaric acid, maleic acid, malic acid, mandelic acid, ascorbic acid, oxalic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, cyclohexylsulfamic acid, or p-toluenesulfonic acid. Pharmaceutically acceptable bases include alkali metals, e.g., sodium or potassium, and alkaline earth metals, e.g., calcium or magnesium, hydroxides, and organic bases, e.g., alkylamines, arylalkylamines, and heterocyclic amines.

[0024] As used herein, the abbreviation "D" stands for deuterium (heavy hydrogen or 2 "H" refers to a stable isotope of hydrogen that is hydrogen (H). Such examples of "D" include an amount of deuterium that exceeds the naturally occurring distribution of deuterium. In some embodiments, D has a deuterium enrichment of about 1% or more. In other embodiments, D has a deuterium enrichment of about 5% or more. In further embodiments, D has a deuterium enrichment of about 10% or less. In still other embodiments, D has a deuterium enrichment of about 20% or less. In still other embodiments, D has a deuterium enrichment of about 30% or less. In still other embodiments, D has a deuterium enrichment of about 40% or less. In still other embodiments, D has a deuterium enrichment of about 50% or more. In still other embodiments, D has a deuterium enrichment of about 60% or more. In other embodiments, D has a deuterium enrichment of about 70% or less. In still other embodiments, D has a deuterium enrichment of about 80% or less. In still other embodiments, D has a deuterium enrichment of about 90% or more. In still other embodiments, D has a deuterium enrichment of about 98% or more. In yet further embodiments, D has a deuterium enrichment of about 99% or greater, hi yet other embodiments, D has a deuterium enrichment of at least 99%.

[0025] This study found that a non-deuterated domperidone formulation reduced the potentially fatal corrected QT interval (QT c Without being bound by any particular theory, QT prolongation may be due to the relatively high C observed with non-deuterated domperidone formulations. max It is speculated that this may be related to

[0026] The pharmaceutical formulations comprising d4-domperidone described herein exhibit various unexpected effects when administered in vivo. In some embodiments, these pharmaceutical formulations exhibit a reduced C max In other embodiments, these pharmaceutical formulations provide a reduction in AUC compared to formulations containing domperidone. In further embodiments, these pharmaceutical formulations provide a reduction in C max and comparable AUC. Furthermore, as disclosed herein, the described d4-domperidone formulations have much higher bioavailability compared to non-deuterated domperidone.

[0027] The pharmaceutical formulation comprises about 1 to about 20% (w / w) d4-domperidone by weight of the formulation. In some embodiments, the pharmaceutical formulation comprises about 2 to about 19% (w / w), about 3 to about 18% (w / w), about 4 to about 17% (w / w), about 5 to about 16% (w / w), about 6 to about 15% (w / w), about 7 to about 15% (w / w), about 8 to about 14% (w / w), about 9 to about 13% (w / w), about 10 to about 12% (w / w). ), about 5 to about 15% (w / w), about 5 to about 14% (w / w), about 5 to about 13% (w / w), about 5 to about 12% (w / w), about 5 to about 11% (w / w), about 5 to about 10% (w / w), about 5 to about 9% (w / w), about 1 to about 15% (w / w), or about 1 to about 10% (w / w) d4-domperidone. In other embodiments, the pharmaceutical formulation comprises about 5 to about 12% (w / w) d4-domperidone. In further embodiments, the pharmaceutical formulation comprises about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20% (w / w) d4-domperidone. In yet other embodiments, the pharmaceutical formulation comprises about 10% (w / w) d4-domperidone.

[0028] The amount of d4-domperidone in the pharmaceutical formulation may also be expressed by amount. In some embodiments, the pharmaceutical formulation contains about 1 to about 50 mg of d4-domperidone. In other embodiments, the pharmaceutical formulation contains about 5 to about 45 mg, about 10 to about 40 mg, about 15 to about 35 mg, about 20 to about 30 mg, about 1 to about 45 mg, about 1 to about 40 mg, about 1 to about 35 mg, about 1 to about 30 mg, about 1 to about 25 mg, about 1 to about 20 mg, about 1 to about 15 mg, about 5 to about 50 mg, about 5 to about 40 mg, about 5 to about 35 mg, about 5 to about 30 mg, about 5 to about 25 mg, about 5 to about 20 mg, about 5 to about 15 mg, about 10 to about 50 mg, about 20 to about 50 mg, about 30 to about 50 mg, or about 40 to about 50 mg of d4-domperidone. In further embodiments, the pharmaceutical formulation comprises about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23. about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, or about 50 mg of d4-domperidone.

[0029] D4-Domperidone formulations containing glyceryl stearate and medium-chain triglycerides

[0030] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising d4-domperidone or a pharma- ceutically acceptable salt thereof, glyceryl stearate, and a medium chain triglyceride.

[0031] As one component, the pharmaceutical formulation includes glyceryl stearate. As used herein, the term "glyceryl stearate" refers to a compound having a glyceryl moiety and a stearic acid moiety, as shown below, which are combined to form a chemically stable molecule. [ka]

[0032] In some embodiments, the glyceryl stearate is glyceryl palmitostearate. In other embodiments, the glyceryl stearate is glycerol distearate. In further embodiments, the glyceryl stearate is glyceryl distearate. In yet other embodiments, the pharmaceutical formulation may include a combination of glyceryl stearates. Thus, the pharmaceutical formulation may include one, two, three, four, or more glyceryl stearates. In some embodiments, the pharmaceutical formulation includes glyceryl palmitostearate and glyceryl distearate. In other embodiments, the pharmaceutical formulation includes glyceryl palmitostearate and glyceryl distearate. In further embodiments, the pharmaceutical formulation includes glycerol distearate and glyceryl distearate. In yet other embodiments, the pharmaceutical formulation includes glyceryl palmitostearate, glycerol distearate, and glyceryl distearate. In yet other embodiments, the glyceryl stearate is Precirol® ATO 5.

[0033] The pharmaceutical formulation comprises about 2 to about 20% (w / w) glyceryl stearate based on the weight of the formulation. In some embodiments, the pharmaceutical formulation comprises about 5 to about 15% (w / w) glyceryl stearate. In further embodiments, the pharmaceutical formulation comprises about 6 to about 14% (w / w), about 7 to about 13% (w / w), about 8 to about 12% (w / w), about 9 to about 11% (w / w), or about 5 to about 15% (w / w) glyceryl stearate. In other embodiments, the pharmaceutical formulation comprises about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, or about 15% (w / w) glyceryl stearate. In yet other embodiments, the pharmaceutical formulation comprises about 9% (w / w) glyceryl stearate. In yet other embodiments, the pharmaceutical formulation comprises about 10% (w / w) glyceryl stearate.

[0034] The term "medium chain triglyceride" as used herein refers to a triglyceride in which the fatty acid moiety has an aliphatic tail of about 6 to about 12 carbon atoms. In some embodiments, the fatty acid moiety has an aliphatic tail of 6, 7, 8, 9, 10, 11, or 12 carbon atoms. In further embodiments, the aliphatic tails of the fatty acids are the same. In other embodiments, the aliphatic tails of the fatty acids are different. In still other embodiments, the fatty acid has an aliphatic tail of 6 carbon atoms, i.e., the medium chain triglyceride is caproic acid. In still other embodiments, the fatty acid has an aliphatic tail of about 8 carbon atoms, i.e., the medium chain triglyceride is caprylic acid. In other embodiments, the fatty acid has an aliphatic tail of about 10 carbon atoms, i.e., the medium chain triglyceride is capric acid. In a further embodiment, the fatty acid has an aliphatic tail of about 12 carbon atoms, i.e., the medium chain triglyceride is lauric acid.

[0035] The medium chain triglycerides are present in the pharmaceutical formulation at about 70 to about 90% (w / w) based on the weight of the formulation. In some embodiments, the pharmaceutical formulation comprises about 72 to about 88% (w / w), about 74 to about 86% (w / w), about 76 to about 84% (w / w), about 78 to about 82% (w / w), about 70 to about 85% (w / w), about 70 to about 80% (w / w), about 75 to about 90% (w / w), about 75 to about 85% (w / w), about 75 to about 80% (w / w), about 80 to about 90% (w / w), about 80 to about 85% (w / w), or about 80 to about 90% (w / w) medium chain triglycerides. In further embodiments, the pharmaceutical formulation comprises about 80 to about 85% (w / w) medium chain triglycerides. In other embodiments, the pharmaceutical formulation comprises about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, or about 90% (w / w) of medium chain triglycerides. In yet other embodiments, the pharmaceutical formulation comprises about 90% (w / w) medium chain triglycerides. In yet other embodiments, the pharmaceutical formulation comprises about 91% (w / w) medium chain triglycerides.

[0036] In some embodiments, the pharmaceutical formulation comprises about 1 to about 20% (w / w) d4-domperidone or a pharma- ceutical acceptable salt thereof, about 2 to about 20% (w / w) glyceryl stearate, and about 70 to about 90% (w / w) medium chain triglycerides. In other embodiments, the pharmaceutical formulation comprises about 5 to about 15% (w / w) d4-domperidone or a pharma- ceutical acceptable salt thereof, about 5 to about 15% (w / w) glyceryl stearate, and about 80 to about 85% (w / w) medium chain triglycerides. Additionally, the pharmaceutical formulation comprises about 10% (w / w) glyceryl stearate and about 90% (w / w) medium chain triglycerides.

[0037] D4-Domperidone formulation containing stearoyl polyoxylglycerides, non-ionic poly(ethylene oxide) polymers, and medium-chain triglycerides

[0038] The present disclosure also provides a pharmaceutical formulation comprising d4-domperidone or a pharma- ceutically acceptable salt thereof, a stearoyl polyoxylglyceride, a non-ionic poly(ethylene oxide) polymer, and a medium chain triglyceride.

[0039] As a first component, the pharmaceutical formulation includes a stearoyl polyoxylglyceride. As used herein, the term "stearoyl polyoxylglyceride" refers to a mixture of glycerol esters and polyethylene glycol. Typically, the polyethylene glycol has an average molecular weight (M) of about 350 to about 1700. n) In some embodiments, the polyethylene glycol has an M of about 400 to about 1500, about 500 to about 1400, about 600 to about 1300, about 700 to about 1200, about 800 to about 1100, about 400 to about 1300, about 400 to about 1100, about 400 to about 900, about 400 to about 700, about 500 to about 1500, about 700 to about 1500, about 900 to about 1500, about 1100 to about 1500, or about 1300 to about 1500. nIn other embodiments, the polyethylene glycol has an M of about 400, about 450, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950, about 1000, about 1050, about 1100, about 1150, about 1200, about 1250, about 1300, about 1350, about 1400, about 1450, about 1500, about 1550, about 1600, about 1650, or about 1700. n In a further embodiment, the polyethylene glycol has an M of about 1450 to about 1550. n In yet another embodiment, the mixture of polyethylene glycol and glycerol esters is prepared using Gelucire® products (available from Gattefosse), such as Gelucire® 44 / 14 (mono-, di-, triglyceride, PEG-32 (molecular weight about 1450 to about 1550) having a melting range of about 42.5 to about 47.5° C. or lauric acid (CMC) of 72±53 g / mL at about 25° C. 12 ), mono- and diesters of Gelucire® 50 / 13 (mono-, di-, and triglycerides), PEG-32 (M of about 1450 to about 1550) n )(Palmitic acid (C 16 ) and stearic acid (C 18 ), with a melting range of about 46 to about 51°C, a hydrophilic-lipophilic balance (HLB) of about 13, and a CMC of about 100 mg / L at about 25°C. 8-18) having a melting range of about 42 to about 46° C., and / or an HLB of about 1; or Gelucire® 48 / 16 (including PEG-32 (molecular weight about 1450 to about 1550) esters of fatty acids having a melting range of about 46 to about 50° C., an HLB of about 16, and / or a CMC of 153±31 mg / L at about 25° C.). In some embodiments, the stearoyl polyoxylglycerides include mono-, di-, and triesters of glycerol. In other embodiments, the stearoyl polyoxylglycerides include mono- and diesters of polyethylene glycol. In further embodiments, the stearoyl polyoxylglycerides include (i) mono-, di-, and / or triesters of glycerol, and (ii) mono- and / or diesters of polyethylene glycol. In yet another embodiment, the stearoyl polyoxyl glyceride is stearoyl polyoxyl-32 glyceride (containing 32 repeating oxyethylene units). In yet another embodiment, the stearoyl polyoxyl glyceride is Gelucire® 50 / 13.

[0040] The pharmaceutical formulation comprises about 3 to about 15% (w / w) stearoyl polyoxylglyceride based on the weight of the formulation. In some embodiments, the pharmaceutical formulation comprises about 4 to about 14% (w / w), about 5 to about 13% (w / w), about 6 to about 12% (w / w), about 7 to about 11% (w / w), about 8 to about 10% (w / w), about 5 to about 12% (w / w), about 5 to about 10% (w / w), or about 6 to about 8% (w / w). In other embodiments, the pharmaceutical formulation comprises about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, or about 15% (w / w) stearoyl polyoxylglyceride. In a further embodiment, the pharmaceutical formulation comprises about 7% (w / w) stearoyl polyoxylglyceride.

[0041] The pharmaceutical formulation also includes a non-ionic poly(ethylene oxide) polymer. As used herein, the term "non-ionic poly(ethylene oxide)" refers to a polymer having the following structure that is liquid at room temperature: [ka] In some embodiments, n is about 2,000 to about 100,000. In other embodiments, n is about 2,000 to about 90,000, about 2,000 to about 80,000, about 2,000 to about 60,000, about 2,000 to about 40,000, about 2,000 to about 20,000, about 2,000 to about 10,000, about 2,000 to about 8,000, about 2,000 to about 6,000, about 2,000 to about 4,000, about 4,000 to about 100,000, or about 8 ,000 to about 100,000, about 10,000 to about 100,000, about 20,000 to about 100,000, about 40,000 to about 100,000, about 60,000 to about 100,000, about 80,000 to about 100,000, about 4,000 to about 80,000, about 6,000 to about 60,000, about 8,000 to about 40,000, and about 10,000 to about 20,000. In further embodiments, n is about 2,000, about 3,000, about 4,000, about 5,000, about 6,000, about 7,000, about 8,000, about 9,000, about 10,000, about 15,000, about 20,000, about 25,000, about 30,000, about 35,000, about 40,000, about 45,000, about 50,000, about 55,000, about 60,000, about 65,000, about 70,000, about 75,000, about 80,000, about 85,000, about 90,000, about 95,000, or about 100,000.

[0042] In some embodiments, the non-ionic poly(ethylene oxide) polymer has a molecular weight (M wIn other embodiments, the nonionic poly(ethylene oxide) has an aryl group of about 500,000 to about 8,000,000, about 600,000 to about 8,000,000, about 700,000 to about 8,000,000, about 800,000 to about 8,000,000, about 900,000 to about 8,000,000, about 1 ,000,000 to about 8,000,000, about 2,000,000 to about 8,000,000, about 3,000,000 to about 8,000,000, about 4,000,000 to about 8,000,000, about 5,000,000 to about 8,000,000, about 6,000,000 to about 8,000,000 w In further embodiments, the nonionic poly(ethylene oxide) polymer has an M of about 500,000, about 600,000, about 700,000, about 800,000, about 900,000, about 1 million, about 2 million, about 3 million, about 4 million, about 5 million, about 6 million, about 7 million, or about 8 million. w In yet another embodiment, the non-ionic poly(ethylene oxide) has an M of about 7,000,000. w In yet another embodiment, the non-ionic poly(ethylene oxide) is polyethylene oxide 303. In yet another embodiment, the non-ionic poly(ethylene oxide) is POLYOX® WSR 303.

[0043] The non-ionic poly(ethylene oxide) polymer is present in the pharmaceutical formulation at about 5 to about 40% (w / w) based on the weight of the formulation. In some embodiments, the pharmaceutical formulation comprises about 10 to about 35% (w / w), about 15 to about 30% (w / w), about 20 to about 25% (w / w), about 5 to about 35% (w / w), about 5 to about 30% (w / w), about 5 to about 25% (w / w), about 5 to about 20% (w / w), or about 5 to about 15% (w / w). The pharmaceutical formulation comprises about 5 to about 10% (w / w), about 10 to about 40% (w / w), about 10 to about 30% (w / w), about 10 to about 20% (w / w), about 10 to about 25% (w / w), about 5 to about 35% (w / w), about 5 to about 30% (w / w), about 5 to about 25% (w / w), or about 5 to about 20% (w / w) of the non-ionic poly(ethylene oxide) polymer. In other embodiments, the pharmaceutical formulation comprises about 12 to about 25% (w / w) of the non-ionic poly(ethylene oxide) polymer. In other embodiments, the pharmaceutical formulation comprises about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40% (w / w) non-ionic poly(ethylene oxide) polymer. In a further embodiment, the pharmaceutical formulation comprises about 19% (w / w) non-ionic poly(ethylene oxide) polymer.

[0044] The pharmaceutical formulation further comprises a medium chain triglyceride as defined above. In some embodiments, the fatty acid moiety has an aliphatic tail having about 6, 7, 8, 9, 10, 11, or 12 carbon atoms. In further embodiments, the medium chain triglyceride is caproic acid. In other embodiments, the medium chain triglyceride is caprylic acid. In yet other embodiments, the medium chain triglyceride is capric acid. In yet other embodiments, the medium chain triglyceride is lauric acid.

[0045] The medium chain triglycerides are present in the pharmaceutical formulation at about 40 to about 80% (w / w), based on the weight of the formulation. In some embodiments, the pharmaceutical formulation comprises about 45 to about 75% (w / w), about 50 to about 70% (w / w), about 55 to about 65% (w / w), about 50 to about 80% (w / w), about 60 to about 80% (w / w), about 70 to about 80% (w / w), about 40 to about 70% (w / w), about 40 to about 60% (w / w), or about 50 to about 70% (w / w) of medium chain triglycerides. In further embodiments, the pharmaceutical formulation comprises about 50 to about 68% (w / w) of medium chain triglycerides. In other embodiments, the pharmaceutical formulation is about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, or about 80% (w / w) medium chain triglycerides. In yet another embodiment, the pharmaceutical formulation comprises about 64% (w / w) medium chain triglycerides.

[0046] In some embodiments, the pharmaceutical formulation comprises, by weight of the formulation, about 1 to about 20% (w / w) d4-domperidone or a pharma- ceutical acceptable salt thereof, about 3 to about 15% (w / w) stearoyl polyoxyl glyceride, about 5 to about 40% (w / w) non-ionic poly(ethylene oxide) polymer, and about 40 to about 80% (w / w) medium chain triglyceride. In other embodiments, the pharmaceutical formulation comprises, by weight of the formulation, about 5 to about 10% (w / w) d4-domperidone or a pharma-ceutical acceptable salt thereof, about 5 to about 10% (w / w) stearoyl polyoxyl glyceride, about 12 to about 25% (w / w) non-ionic poly(ethylene oxide) polymer, and about 50 to about 68% (w / w) medium chain triglyceride.

[0047] D4-Domperidone formulations containing non-ionic poly(ethylene oxide) polymers and polyethylene glycol

[0048] In a further embodiment, the present disclosure provides a pharmaceutical formulation comprising d4-domperidone, or a pharma- ceutically acceptable salt thereof, a non-ionic poly(ethylene oxide) polymer, and polyethylene glycol.

[0049] As one component, the pharmaceutical formulation comprises a non-ionic poly(ethylene oxide) polymer as defined above. In some embodiments, the non-ionic poly(ethylene oxide) is polyethylene oxide 303. In further embodiments, the non-ionic poly(ethylene oxide) is POLYOX® WSR303.

[0050] The non-ionic poly(ethylene oxide) polymer is present in the pharmaceutical formulation at about 5 to about 30% (w / w), based on the weight of the formulation. In some embodiments, the pharmaceutical formulation comprises about 10 to about 30% (w / w), about 15 to about 30% (w / w), about 20 to about 25% (w / w), about 5 to about 30% (w / w), about 5 to about 25% (w / w). About 5 to about 20% (w / w), about 5 to about 15% (w / w), about 5 to about 10% (w / w), about 10 to about 20% (w / w), about 10 to about 25% (w / w), or about 5 to about 20% (w / w) of the non-ionic poly(ethylene oxide) polymer. In other embodiments, the pharmaceutical formulation comprises about 10 to about 20% (w / w) of the non-ionic poly(ethylene oxide) polymer. In further embodiments, the pharmaceutical formulation comprises about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30% (w / w) non-ionic poly(ethylene oxide) polymer. In yet other embodiments, the pharmaceutical formulation comprises about 15% (w / w) non-ionic poly(ethylene oxide) polymer.

[0051] The pharmaceutical formulation also includes polyethylene glycol. As used herein, the term "polyethylene glycol" refers to a chemical compound that is liquid at room temperature and has the following structure, where m is from about 7 to about 20: [ka] In some embodiments, m is about 7 to about 15, about 7 to about 10, about 8 to about 15, about 8 to about 10, about 9 to about 15, or about 9 to about 13. In other embodiments, m is about 8 to about 9. In further embodiments, m is about 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20. In yet other embodiments, m is about 8. In yet other embodiments, m is about 9. Polyethylene glycols also include those having a molecular weight (M) of about 300 to about 1,000. w) In some embodiments, the polyethylene glycol has an M of about 400 to about 900, about 500 to about 800, about 600 to about 700, about 300 to about 900, about 300 to about 800, about 300 to about 700, about 300 to about 600, about 300 to about 500, about 400 to about 1,000, about 500 to about 1,000, about 600 to about 1,000, about 700 to about 1,000, about 800 to about 1,000, or about 900 to about 1,000. w In further embodiments, the polyethylene glycol has an M of about 400, about 450, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950, or about 1,000. w In yet another embodiment, the polyethylene glycol has an M of about 400. w In yet another embodiment, the polyethylene glycol is polyethylene glycol 400.

[0052] The pharmaceutical formulation comprises about 70 to about 90% (w / w) polyethylene glycol based on the weight of the formulation. In some embodiments, the pharmaceutical formulation comprises about 70 to about 85% (w / w), about 70 to about 80% (w / w), about 70 to about 75% (w / w), about 75 to about 90% (w / w), about 80 to about 90% (w / w), or about 85 to about 90% (w / w) polyethylene glycol. In other embodiments, the pharmaceutical formulation comprises about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, or about 90% (w / w) polyethylene glycol. In a further embodiment, the pharmaceutical formulation comprises about 75% (w / w) polyethylene glycol.

[0053] In some embodiments, the pharmaceutical formulation comprises, by weight of the formulation, about 1 to about 20% (w / w) d4-domperidone or a pharma- ceutical acceptable salt thereof, about 5 to about 30% (w / w) non-ionic poly(ethylene oxide) polymer, and about 70 to about 90% (w / w) polyethylene glycol. In other embodiments, the pharmaceutical formulation comprises, by weight of the formulation, about 5 to about 10% (w / w) d4-domperidone or a pharma- ceutical acceptable salt thereof, about 10 to about 20% (w / w) non-ionic poly(ethylene oxide) polymer, and about 70 to about 80% (w / w) polyethylene glycol.

[0054] The pharmaceutical formulations described herein may also include one or more antioxidants. In some embodiments, the pharmaceutical formulation includes one antioxidant. In other embodiments, the pharmaceutical formulation includes two antioxidants. In further embodiments, the pharmaceutical formulation includes three antioxidants. The antioxidant can be selected by one of skill in the art. In some embodiments, the antioxidant is ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, potassium metabisulfite, sodium metabisulfite, sodium thiosulfate, or vitamin E. In further embodiments, the antioxidant is BHT. In yet other embodiments, the antioxidant is BHA and BHT.

[0055] The total amount of antioxidants in the pharmaceutical formulation is about 0.01 to about 0.5% (w / w) based on the total weight of the formulation. In some embodiments, the amount of one or more antioxidants in the pharmaceutical formulation is about 0.01 to about 0.4, about 0.01 to about 0.3, about 0.01 to about 0.2, about 0.01 to about 0.1, about 0.01 to about 0.05, about 0.05 to about 0.4, about 0.05 to about 0.3, about 0.05 to about 0.2, or about 0.05 to about 0.1% (w / w). In other embodiments, the pharmaceutical formulation comprises about 0.01, about 0.02, about 0.03, about 0.04, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, about 0.10, about 0.11, about 0.12, about 0.013, about 0.014, about 0.015, about 0.016, about 0.017, about 0.018, about 0.019, about 0.20, about 0.21, about 0.22, about 0.23, about 0.24, about 0.25, about 0.26, about 0.27, about 0.28, about 0.29, about 0.30, about 0.31, about 0.32, about 0.33, about 0.34, about 0.35, about 0.36, about 0.37, about 0.38, about 0.39, about 0.40, about 0.41, about 0.42, about 0.43, about 0.44, about 0.45, about 0.46, about 0.47, about 0.48, about 0.49, or about 0.50% (w / w). In further embodiments, the pharmaceutical formulation comprises about 0.1% (w / w) antioxidant. In yet other embodiments, the pharmaceutical formulation comprises about 0.05% (w / w) antioxidant. In yet other embodiments, the pharmaceutical formulation comprises about 0.15% (w / w) antioxidant. In other embodiments, the pharmaceutical formulation comprises about 0.1% (w / w) BHA. In further embodiments, the pharmaceutical formulation comprises about 0.05% (w / w) BHT. In yet other embodiments, the pharmaceutical formulation comprises about 0.1% (w / w) BHA and about 0.05% (w / w) BHT.

[0056] The d4-domperidone formulations described herein are useful in a variety of therapeutic methods, including, but not limited to, methods for treating disorders that are gastroparesis, nausea separate from gastroparesis, vomiting separate from gastroparesis, nausea associated with gastroparesis, vomiting associated with gastroparesis, gastroesophageal reflux disease, insufficient lactation, chemotherapy-associated nausea and / or vomiting, or combinations thereof. The methods comprise administering to a patient a pharmaceutical formulation described herein. In some embodiments, the methods are useful for treating gastroparesis. In other embodiments, the methods are useful for treating nausea separate from gastroparesis. In further embodiments, the methods are useful for treating vomiting separate from gastroparesis. In still other embodiments, the methods are useful for treating nausea associated with gastroparesis. In still other embodiments, the methods are useful for treating vomiting associated with gastroparesis. In other embodiments, the methods are useful for treating gastroesophageal reflux disease. In further embodiments, the methods are useful for treating insufficient lactation. In still other embodiments, the methods are useful for treating chemotherapy-associated nausea and / or vomiting.

[0057] The formulation can be administered by any suitable route for administration of non-deuterated domperidone.In some embodiments, the administration of the pharmaceutical formulation is oral, transdermal, parenteral, or a combination thereof.In further embodiments, the administration is oral.

[0058] The pharmaceutical preparation can be formulated to be administered in solid or liquid form. In some embodiments, the pharmaceutical preparation is formulated in the form of a tablet, caplet, capsule, powder, softgel, suspension or liquid, or a combination thereof. In other embodiments, the pharmaceutical preparation is formulated in the form of a tablet. In further embodiments, the pharmaceutical preparation is formulated in the form of a caplet. In still other embodiments, the pharmaceutical preparation is formulated in the form of a capsule. In still other embodiments, the pharmaceutical preparation is formulated in the form of a powder. In other embodiments, the pharmaceutical preparation is formulated in the form of a softgel. In further embodiments, the pharmaceutical preparation is formulated in the form of a suspension. In still other embodiments, the pharmaceutical preparation is formulated in the form of a liquid.

[0059] The following examples are provided to illustrate some of the concepts described within this disclosure. Each example is believed to provide a specific individual embodiment of the formulation, method of preparation, and use, but no example should be considered as limiting the more general embodiments described herein.

[0060] In the following examples, efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. max = maximum plasma concentration, t max = Time to maximum plasma concentration, MRT last = average residence time calculated up to the last observable time point, AUC last = area under the curve calculated up to the last observable time point. EXAMPLES

[0061] Example 1: Preparation of formulations Five formulations (A to E) containing d4-domperidone were prepared by combining the ingredients in Table 1. [Table 1]

[0062] Formulations AC and E were formulated as liquids or semisolids and filled into capsules, while Formulation D was compressed into tablets using a single station Carver press. EXAMPLES

[0063] Example 2: PK study in dogs using d4-domperidone formulations In this study, male beagle dogs were orally administered various capsule or tablet formulations of d4-domperidone shown in Example 1, and a suspension formulation of domperidone prepared by combining 0.5% Methocel® cellulose ether, 0.2% polysorbate 80 (Tween® 80), and 0.72% lactic acid to evaluate the oral exposure of domperidone and d4-domperidone.

[0064] Each d4-domperidone formulation was administered orally (PO) at 10 mg / dog, and each domperidone formulation was administered at 1 mg / kg. Blood was collected up to 24 hours after dosing, and plasma concentrations of domperidone or domperidone-d4 were measured by LCMS / MS. Pharmacokinetic parameters were determined using Phoenix WinNonlin (v8.0) software. Mean plasma concentrations and pharmacokinetic parameters are summarized in Table 2. [Table 2]

[0065] Table 2 shows the measured C max , t max , MRT last , and AUC last The formulation AC is C max Formulation E showed a significant decrease in C, a longer MRT and a comparable AUC compared to formulation F. However, formulation E showed a much higher C compared to formulation F. max and AUC are shown in Figures 1 and 2. EXAMPLES

[0066] Example 3: QT with d4-domperidone c Canine cardiovascular study shows minimization Beagle dogs were used to evaluate the potential cardiovascular effects of non-deuterated domperidone and d4-domperidone, administered by gavage as an oral suspension for comparison.

[0067] In one study, non-deuterated domperidone was evaluated using a formulation of 0.5% Methocel® (hydroxypropyl methylcellulose), 0.2% polysorbate 80 (Tween® 80), 0.72% lactic acid in sterile water for injection, USP. The d4-domperidone formulation was Formulation A, Example 1. For non-deuterated domperidone, formulations were prepared by mixing an appropriate amount of carrier with an appropriate amount of non-deuterated domperidone to achieve nominal concentrations of 0.2, 1, and 4 mg / mL. Beagle dogs were dosed in a volume of 5 mL / kg by oral gavage to provide doses of 1, 5, and 20 mg / kg, as well as a carrier control. See Table 3. One animal / treatment was dosed weekly with at least a 2-day washout period between doses until each animal had received all treatments. The same four animals received treatments according to a Latin Square design. Systolic and diastolic blood pressure, heart rate and Lead II electrocardiogram were recorded continuously starting 1.5 h before dosing and all parameters were recorded continuously 24 h after the end of dosing in the last animal. [Table 3]

[0068] Corrected values ​​for individual animals (QT c VdW) was calculated using the Van de Water formula. When corrected using the Van de Water formula, the QT interval was significantly longer at doses of 5 and 20 mg / kg when non-deuterated domperidone was administered. c VdW increased to 23 and 21 msec, respectively.

[0069] Table 4 shows the change (% and ms) from appropriate time-matched controls for each treatment of deuterated domperidone. [Table 4]

[0070] For deuterated domperidone, male dogs were orally administered either alone or with the carrier (0 mg; capsule) and capsules containing d4-domperidone at doses of 20, 110 or 385 mg. One animal / treatment was administered each week, with a washout period of at least 3 days between doses, until each animal had received all treatments; see Table 5. The same five animals received all treatments according to a Latin square design with a washout period of at least 3 days between treatments. Body temperature, blood pressure, heart rate, and electrocardiogram (ECG) were monitored continuously for at least 2 hours before and at least 24 hours after dosing. [Table 5]

[0071] Three days prior to the study and during the stock colony (10 days prior to the first dose), body temperature and cardiovascular endpoints were monitored continuously for at least 24 hours. These data were collected at 1-minute intervals. The first 24 hours of data were used to calculate the QTc interval. Body temperature, blood pressure, heart rate (calculated from blood pressure and ECG), and ECG were monitored continuously from at least 2 hours prior to dosing until at least 24 hours after dosing. Data were collected and analyzed at 1-minute intervals and reported at 15-minute intervals. QT cIntervals were calculated using a procedure based on that described by Spence ("The heart rate corrected QT interval of conscious beagle dogs: a formula based on analysis of covariance," Toxicol Sci, 1998;45:247 258) and corrected by Miyazaki and Tagawa ("Rate-correction technique for QT interval in long term telemetry ECG recording in beagle dogs," Exp. Anim., 2002;51:465 475). Exposure was confirmed by drawing blood (approximately 1 mL) from the jugular vein 8 and 24 hours after dosing.

[0072] After administration of 110 mg and 385 mg, the QT interval was time-dependent c Increases in intervals were observed, but the magnitude was similar between doses. For each time interval from 9 to 20 hours after the 110 mg and 385 mg doses, the maximum increase was 13% (30 ms) compared with time-matched vehicle, which demonstrated statistical significance. Table 6 shows the change (% and ms) from the appropriate time-matched control group for each d4-domperidone dose group. [Table 6]

[0073] Figures 9 and 10 show that different doses of d4-domperidone and non-deuterated domperidone significantly improved the QT c The graph shows the effect of the low dose of the non-deuterated formulation on the QT c This shows that the effect of QT at the maximum plasma concentration is large. c This is also evident in Figures 11 and 12, which show the impact of the changes. EXAMPLES

[0074] Example 4: Comparison of PK parameters of d4-Domperidone and suspension formulations of Domperidone C of domperidone and d4-domperidone administered at different doses to dogs max and AUC values ​​were compared. Data for non-deuterated domperidone were obtained as described by Heykants in "On the pharmacokinetics of domperidone in animals and man I. Plasma levels of domperidone in rats and dogs". Dogs were administered capsules containing different amounts of domperidone as described in "Age related absorption and passage through the blood brain barrier in rats" European J. of Drug Metabolism and Pharmacokinetics, 1981, 6(1):27-36 (hereby incorporated by reference).

[0075] A d4-domperidone suspension formulation was prepared containing 0.5% Methocel, 0.1% polysorbate 80 and 0.72% lactic acid. The d4-domperidone suspension was then administered to the dogs described in Example 2 or 3 at different doses as shown in Table 7. [Table 7]

[0076] According to the data shown in Table 7 and Figure 8, d4-domperidone had a higher C max The bioavailability was found to be significantly higher, including higher (4- to 5-fold) and AUC (2- to 4-fold). EXAMPLES

[0077] Example 5: C max PK study of slowing down In this study, oral exposure of domperidone and d4-domperidone was evaluated in male beagle dogs following oral administration of capsules containing formulations A and B of d4-domperidone separately from Example 1 and a suspension formulation of domperidone prepared by combining 0.5% Methocel® cellulose ether, 0.2% polysorbate 80 (Tween® 80) and 0.72% lactic acid. The composition of the d4-domperidone formulations (A and B) is repeated in Table 8. [Table 8]

[0078] The d4-domperidone formulation was orally administered at 10 mg / dog and the domperidone formulation at 1 mg / kg. Blood was collected up to 24 hours after administration, and the plasma concentrations of domperidone or d4-domperidone were measured by LCMS / MS. Pharmacokinetic parameters were determined using Phoenix WinNonlin (v8.0) software. The mean plasma concentrations and pharmacokinetic parameters are summarized in Table 9. [Table 9]

[0079] See Figure 5. These data show that Formulation A has a C max , showing that both Formulations A and B showed a significant increase in AUC mean residence time compared to non-layered domperidone. EXAMPLES

[0080] Example 6: PK study in dogs using Formulation A In this study, oral exposure of domperidone and d4-domperidone formulations was evaluated in male beagle dogs. A capsule formulation of d4-domperidone ("Formulation A" in Example 1) and a suspension formulation of domperidone prepared with 0.5% Methocel® cellulose ether, 0.2% polysorbate 80 (Tween® 80), and 0.72% lactic acid were independently prepared, as repeated in Table 10. [Table 10]

[0081] The d4-domperidone formulation was orally administered at 10 mg / dog and the domperidone formulation at 1 mg / kg. Blood was collected up to 36 hours after administration, and the plasma concentrations of domperidone or d4-domperidone were measured by LCMS / MS. Pharmacokinetic parameters were determined using Phoenix WinNonlin (v8.0) software. The mean plasma concentrations and pharmacokinetic parameters are summarized in Table 11. [Table 11]

[0082] See Figure 6. These data show that Formulation A has similar AUC, C max , and an increase in the average residence time. EXAMPLES

[0083] Example 7: Use of antioxidants A study was conducted to evaluate the effect of antioxidants on the degradation of d4-Domperidone. Samples were initially prepared and analyzed, then stored at 60°C and analyzed again after 28 days. A reversed-phase HPLC method was used to quantify impurities in d4-Domperidone. Waters Atlantis dC 18(or equivalent) column, a methanolic ammonium acetate mobile phase, and a UV detector. Table 12 shows the formulations, and Table 13 shows the results for formulations with and without antioxidants. [Table 12] [Table 13]

[0084] These data indicate that the formulations containing antioxidants resist oxidation when heated to 60° C. However, samples without antioxidants showed a significant amount of oxidation when heated to the same temperature. EXAMPLES

[0085] Example 8 D4-Domperidone pharmaceutical formulations were prepared and encapsulated in a GMP encapsulation equipment using the amounts listed in Tables 14-16. Specifically, compounding activities were conducted under nitrogen blanket and yellow light; see Figure 7. Batches were then encapsulated at temperatures of approximately 38.7-51.7°C using a 2C oval die and a single bottom shot wedge with a 0.040 inch hole. Capsules were hand milled using a mixture of medium chain triglycerides and lecithin (97% MCT / 3% lecithin). [Table 14] [Table 15] [Table 16]

[0086] Although the present invention has been described in connection with its preferred specific embodiments, it is to be understood that the foregoing description and the following examples are intended to illustrate, not limit, the scope of the invention. It will be understood by those skilled in the art that various modifications can be made and equivalents can be substituted without departing from the scope of the invention, and that other aspects, advantages, and modifications will become apparent to those skilled in the art to which the invention pertains. In addition to the embodiments described herein, the present invention contemplates and claims those inventions that result from the combination of features of the invention cited herein and features of the cited prior art documents that are complementary to the features of the invention. Similarly, it will be understood that any material, feature, or article described can be used in combination with any other material, feature, or article, and such combinations are considered within the scope of the invention.

[0087] The disclosures of each patent, patent application, and publication cited or described herein are hereby incorporated by reference in their entirety for all purposes.

Claims

1. 1. A pharmaceutical formulation comprising: Based on the weight of the formulation, about 1 to about 10% (w / w) of (i) deuterated d ４ - Domperidone: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof; About 9 to about 20% (w / w) of a non-ionic poly(ethylene oxide) polymer, based on the weight of the formulation: 【Chemistry 2】 wherein the nonionic poly(ethylene oxide) polymer has an M of about 400,000 to about 8,000,000. ｗ and M of about 300 to about 1000 based on the weight of the formulation. ｗ and about 70 to about 90% (w / w) polyethylene glycol having the formula:

2. 10. The pharmaceutical formulation of claim 1, comprising about 70 to about 80% (w / w) or about 75% (w / w) polyethylene glycol based on the weight of the formulation.

3. 3. The pharmaceutical formulation according to claim 1 or 2, wherein the non-ionic poly(ethylene oxide) polymer has an M of about 7,000,000. ｗ 1. A pharmaceutical formulation comprising:

4. In the pharmaceutical formulation according to any one of claims 1 to 3, the polyethylene glycol has an M of about 400. ｗ 1. A pharmaceutical formulation comprising:

5. The pharmaceutical formulation according to any one of claims 1 to 4, further comprising an antioxidant.

6. 6. The pharmaceutical formulation of claim 5, wherein the antioxidant is ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, potassium metabisulfite, sodium metabisulfite, sodium thiosulfate, or vitamin E, or preferably butylated hydroxyanisole or butylated hydroxytoluene.

7. The pharmaceutical formulation according to any one of claims 1 to 6, About 5 to about 12% (w / w) or about 10% (w / w) of d based on the weight of the formulation. ４ - A pharmaceutical preparation comprising domperidone.

8. The pharmaceutical formulation according to any one of claims 1 to 7, wherein the dosage is from about 1 to about 50 mg. ４ - A pharmaceutical preparation comprising domperidone.

9. 9. The pharmaceutical formulation of any one of claims 1 to 8 for use in treating a disorder which is gastroparesis, nausea separate from gastroparesis, vomiting separate from gastroparesis, nausea associated with gastroparesis, vomiting associated with gastroparesis, gastroesophageal reflux disease, lactation failure, or a combination thereof in a patient.

10. 10. The pharmaceutical formulation of claim 9, wherein the formulation is in the form of a tablet, capsule, softgel, suspension, liquid, or a combination thereof.

11. 11. The pharmaceutical formulation of claim 9 or 10, wherein the disorder is gastroparesis.

12. 11. The pharmaceutical formulation of claim 9 or 10, wherein the disorder is gastroesophageal reflux disease.

13. 11. The pharmaceutical formulation according to claim 9 or 10, wherein the disorder is lactation failure.

Images