BR112021007755B1 - FORMULATIONS CONTAINING DOMPERIDONE AND USE THEREOF - Google Patents

Abstract

FORMULATIONS CONTAINING DOMPERIDONE. The disclosure provides pharmaceutical formulations comprising domperidone or a pharmaceutically acceptable salt thereof. The formulations also contain (i) a glyceryl stearate and a medium chain triglyceride; or (ii) a polyoxyl stearoyl glyceride, a nonionic poly(ethylene oxide) polymer and a medium chain triglyceride; or (iii) a nonionic poly(ethylene oxide) polymer and a polyethylene glycol. The disclosure also provides methods for treating a disorder 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 in a patient. , which comprises administering to the patient the formulation defined in this document. In some aspects, the disorder is gastroparesis. In other respects, the disorder is gastroesophageal reflux disease. In other respects, the disorder is insufficient lactation.

Description

REFERENCE FOR RELATED ORDERS

[0001] This application claims the benefit of US Provisional Patent Application No. 62 / 750,480, filed on October 25, 2018, which is incorporated by reference herein.

TECHNICAL FIELD

[0002] This disclosure refers to pharmaceutical formulations containing domperidone.

STATE OF THE TECHNIQUE

[0003] Gastroparesis is a condition in which the motility of the stomach does not work or does not work properly, which prevents the stomach from emptying and interferes with digestion. Treatment of gastroparesis requires medications, for example metoclopramide, erythromycin or cisapride, to stimulate the stomach muscles. Metoclopramide has serious side effects, such as the development of movement disorders or adverse interactions with other medications; erythromycin is susceptible to loss of efficacy as the patient's tolerance to the medication increases; and cisapride has limited accessibility.

[0004] Medications to control nausea and vomiting, for example, prochlorperazine, thiethylperazine, diphenhydramine or ondansetron, can also be administered to treat gastroparesis. Symptoms of gastroparesis can also be treated surgically, such as installing jejunostomy tubes, gastric ventilation tubes, or feeding tubes.

[0005] Domperidone is an effective dopamine antagonist that does not readily cross the blood-brain barrier and can be used to treat gastroparesis. Safe and effective formulations of domperidone are needed.

SUMMARY

[0006] In some embodiments, the disclosure provides pharmaceutical formulations comprising domperidone or a pharmaceutically acceptable salt thereof, a glyceryl stearate and a medium chain triglyceride.

[0007] In other embodiments, the disclosure also provides pharmaceutical formulations comprising domperidone or a pharmaceutically acceptable salt thereof, a polyoxyl stearoyl glyceride, a nonionic poly(ethylene oxide) polymer, and a medium chain triglyceride.

[0008] In other embodiments, the disclosure provides pharmaceutical formulations comprising domperidone or a pharmaceutically acceptable salt thereof, a nonionic poly(ethylene oxide) polymer, and a polyethylene glycol.

[0009] In still other embodiments, the disclosure provides methods for treating a disorder 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 in a patient, comprising administering to the patient the formulation defined herein. In some aspects, the disorder is gastroparesis. In other respects, the disorder is gastroesophageal reflux disease. In other respects, the disorder is insufficient lactation.

[0010] Other aspects and embodiments of the invention will be readily apparent from the following detailed description of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The present application is even better understood when read in conjunction with the attached drawings. For the purpose of illustrating the subject matter of the invention, exemplary embodiments of the subject matter of the invention are shown in the figures; however, the subject matter of the presently disclosed invention is not limited to the specific compositions, methods, devices and systems disclosed. Furthermore, drawings are not necessarily drawn to scale.

[0012] FIG. 1 is a flow chart for the filling composition of 5 mg and 10 mg domperidone samples.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0013] In the disclosure, the singular forms "a", "an" and "the" include the plural reference and the reference to a particular numerical value includes at least that specific value, unless the context clearly indicates the contrary. Thus, for example, a reference to "a material" is a reference to at least one such material and equivalents thereof known to those skilled in the art, and so on.

[0014] When a value is expressed as an approximation by use of the description "about", it will be understood that the particular value forms another modality. In general, the use of the term "about" indicates approximations that may vary depending on the desired properties sought to be obtained by the disclosed matter and should be interpreted in the specific context in which it is used, based on its function. One skilled in the art will be able to interpret this as a matter of routine. In some cases, the number of significant figures used for a given value may be a non-limiting method for determining the length of the word "about". In other cases, the gradations used in a series of values can be used to determine the intended range available for the term "about" for each value. Where present, all ranges are inclusive and combinable. That is, references to values declared in ranges include all values within that range.

[0015] When a list is presented, unless otherwise indicated, it should be understood that each individual element of that list and each combination of that list should be interpreted as a separate modality. For example, a list of modalities presented as "A, B, or C" should be interpreted as including the modalities "A", "B", "C", "A or B", "A or C", "B or C” or “A, B or C.”

[0016] It should be appreciated that certain features of the invention that are, for greater clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, unless it is obviously incompatible or excluded, each individual modality is considered combinable with any other modality(s) and that combination is considered another modality. On the other hand, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination. It should also be noted that claims may be written to exclude an optional element. Accordingly, this statement is intended to serve as an antecedent basis for the use of proprietary terminology such as "only", "only" and the like in connection with the citation of claim elements or the use of a "negative" limitation. Finally, although a modality can be described as part of a series of steps or part of a more general structure, each said step can also be considered an independent modality in itself.

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

[0018] "Treating" or variations thereof refers to the elimination or reduction of at least one physical parameter of the disease or disorder.

[0019] "Domperidone", as referenced herein, refers to 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, in which all atoms are present in their naturally occurring amounts:

[0020] Any reference to domperidone may also include, where noted, pharmaceutically acceptable salts, esters, hydrates, solvates, prodrug forms and derivatives thereof, which are broadly defined as compounds of domperidone that are modified or partially substituted, Examples include, but are not limited to, addition of a single atom, addition of a reactive group, addition of a functional group, formation of a dimer or multimer, conjugation with another molecule such as an antibody, etc.

[0021] "Pharmaceutically acceptable" refers to properties and/or substances that are acceptable to the patient from a pharmacological/toxicological advantage and to the manufacturing pharmaceutical chemist from a physical/chemical advantage in relation to the composition, formulation, stability, patient acceptance and bioavailability.

[0022] A pharmaceutically acceptable salt includes salts with a pharmaceutically acceptable acid or base, for example, inorganic acids, for example, hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, hydroiodric and nitric acids, and organic acids, for example citric, fumaric, maleic, malic, mandelic acid ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methanesulfonic, ethanesulfonic, benzenesulfonic, cyclohexylsulfamic (cyclamic) or p-toluenesulfonic acid. Pharmaceutically acceptable bases include alkali metal, for example, sodium or potassium, and alkaline earth metal, for example, calcium or magnesium, hydroxides and organic bases, for example, alkylamines, arylalkylamines and heterocyclic amines.

[0023] The pharmaceutical formulations containing domperidone, described herein, exhibit a variety of unexpected effects when administered in vivo. In some embodiments, these pharmaceutical formulations result in a reduced Cmax compared to other domperidone formulations in the prior art. In other embodiments, these pharmaceutical formulations result in a reduction in AUC compared to other domperidone formulations in the prior art. In other embodiments, these pharmaceutical formulations result in a reduced Cmax and a comparable AUC. Furthermore, as described herein, the described domperidone formulations have a much greater bioavailability compared to other domperidone formulations in the prior art.

[0024] Pharmaceutical formulations contain about 1 to about 20% (w/w), based on the weight of the formulation, of domperidone. In some embodiments, the pharmaceutical formulations contain 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) /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) domperidone. In other embodiments, the pharmaceutical formulations contain about 5 to about 12% (w/w) domperidone. In other embodiments, the pharmaceutical formulations contain 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) domperidone. In still other embodiments, the pharmaceutical formulations contain about 10% (w/w) domperidone.

[0025] The amount of domperidone in pharmaceutical formulations can also be expressed as a quantity. In some embodiments, the pharmaceutical formulations contain about 1 to about 50 mg of domperidone. In other embodiments, the pharmaceutical formulations contain 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 around 50 mg of domperidone. In other embodiments, the pharmaceutical formulations contain 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 domperidone.

[0026] Domperidone Formulations Containing a Glyceryl Stearate and Medium Chain Triglyceride

[0027] In some embodiments, the present disclosure provides pharmaceutical formulations comprising domperidone or a pharmaceutically acceptable salt thereof, a glyceryl stearate and a medium chain triglyceride.

[0028] As a component, pharmaceutical formulations contain a glyceryl stearate. The term "glyceryl stearate" as used herein refers to a compound having glyceryl and stearate components, as shown below, wherein the components are linked to form a chemically stable molecule.

[0029] In some embodiments, the glyceryl stearate is a glyceryl palmitostearate. In other embodiments, the glyceryl stearate is a glycerol distearate. In other embodiments, the glyceryl stearate is a glyceryl distearate. In still other embodiments, the pharmaceutical formulation may contain combinations of glyceryl stearates. Thus, the pharmaceutical formulation may contain 1, 2, 3, 4 or more glyceryl stearates. In some embodiments, the pharmaceutical formulations contain glyceryl palmitostearate and glycerol distearate. In other embodiments, the pharmaceutical formulations contain glyceryl palmitostearate and glyceryl distearate. In other embodiments, the pharmaceutical formulations contain glycerol distearate and glyceryl distearate. In still other embodiments, the pharmaceutical formulations contain glyceryl palmitostearate, glycerol distearate and glyceryl distearate. In still other embodiments, the glyceryl stearate is Precirol® ATO 5.

[0030] Pharmaceutical formulations contain about 2 to about 20% (w/w), based on the weight of the formulation, of glyceryl stearate. In some embodiments, the pharmaceutical formulations contain about 5 to about 15% (w/w) of glyceryl stearate. In other embodiments, the pharmaceutical formulations contain 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 5 to about 15% (w/w) of the glyceryl stearate. In other embodiments, the pharmaceutical formulations contain 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 still other embodiments, the pharmaceutical formulations contain about 9% (w/w) of glyceryl stearate. In still other embodiments, the pharmaceutical formulations contain about 10% (w/w) of glyceryl stearate.

[0031] The term "medium chain triglyceride", as used herein, refers to triglycerides 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 other embodiments, the aliphatic fatty acid tails are the same. In other embodiments, the aliphatic fatty acid tails are different. In still other embodiments, the fatty acid has an aliphatic tail of 6 carbon atoms, that is, the medium chain triglyceride is caproic acid. In still other embodiments, the fatty acid has an aliphatic tail of about 8 carbon atoms, that is, the medium chain triglyceride is caprylic acid. In other embodiments, the fatty acid has an aliphatic tail of about 10 carbon atoms, that is, the medium chain triglyceride is capric acid. In other embodiments, the fatty acid has an aliphatic tail of about 12 carbon atoms, that is, the medium chain triglyceride is lauric acid.

[0032] Medium chain triglyceride is 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 formulations contain 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), of the medium chain triglyceride. In some embodiments, pharmaceutical formulations contain about 80 to about 85% (w/w). /p) of medium chain triglyceride. In other embodiments, the pharmaceutical formulations contain 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 the triglyceride of medium chain. In still other embodiments, the pharmaceutical formulations contain about 90% (w/w) of the medium chain triglyceride. In still other embodiments, the pharmaceutical formulations contain about 91% (w/w) of the medium chain triglyceride.

[0033] In some aspects, pharmaceutical formulations contain about 1 to about 20% (w/w) of domperidone or a pharmaceutically acceptable salt thereof, about 2 to about 20% (w/w) of stearate of glyceryl and about 70 to about 90% (w/w) of medium chain triglyceride. In other aspects, the pharmaceutical formulations contain about 5 to about 15% (w/w) of domperidone or a pharmaceutically acceptable salt thereof, about 5 to about 15% (w/w) of glyceryl stearate and about 80 to about 85% (w/w) of medium chain triglyceride. In other aspects, pharmaceutical formulations contain about 10% (w/w) of glyceryl stearate and about 90% (w/w) of medium chain triglyceride.

[0034] Domperidone formulation containing a polyoxyl stearoyl glyceride, non-ionic poly(ethylene oxide) polymer and medium chain triglyceride

[0035] The present disclosure also provides pharmaceutical formulations comprising domperidone or a pharmaceutically acceptable salt thereof, a polyoxyl stearoyl glyceride, a nonionic poly(ethylene oxide) polymer and a medium chain triglyceride.

[0036] As a first component, pharmaceutical formulations contain a polyoxyl stearoyl glyceride. The term "polyoxyl stearoyl glyceride" as used herein refers to a mixture of glycerol and polyethylene glycol esters. Typically, polyethylene glycol has an average molecular weight (Mn) of about 350 to about 1700. In some embodiments, polyethylene glycol has a Mn 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 of 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. In other embodiments the polyethylene glycol has a Mn 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. According to other embodiments, the polyethylene glycol has a Mn of about 1450 to about 1550. In still other embodiments, the mixture of polyethylene glycol and glycerol esters is a Gelucire® product (available in Gattefosse), such as Gelucire® 44/14 (containing mono-, di- and tri-glycerides and PEG-32 (molecular weight of about 1450 to about 1550) mono- and di-esters of lauric acid (C12) having a melting range of about 42.5 to about 47.5°C, or critical micellar concentration (CMC) of 72 ± 53g/mL at about 25°C), Gelucire® 50/13 (containing mono, di and triglycerides and PEG-32 (Mn of about 1450 to about 1550), mono- and diesters of palmitic (C16) and stearic (C18) acids, a melting range of about 46 to about 51°C, hydrophilic balance lipophilic (HLB) of about 13, CMC of about 100 mg L at about 25°C), Gelucire® 43/01 (containing mono-, di- and tri-glyceride esters of fatty acids (C8-18), a melting range of about 42 to about 46°C, and/or HLB of about 1), or Gelucire® 48/16 (containing PEG-32 (molecular weight of about 1450 to about 1550) fatty acids, a melting range of about 46 to about 50°C, HLB of about 16, and/or CMC of 153 ± 31 mg/L at about 25°C). In some embodiments, a polyoxyl stearoyl glyceride contains glycerol monoesters, diesters, and triesters. In other embodiments, a polyoxyl stearoyl glyceride contains monoesters and diesters of polyethylene glycols. In other embodiments, the polyoxyl stearoyl glyceride contains (i) monoesters, diesters and/or triesters of glycerol and (ii) monoesters and/or diesters of polyethylene glycols. In still other embodiments, the polyoxyl stearoyl glyceride is a polyoxyl-32 stearoyl glyceride (containing 32 oxyethylene repeat units). In still other embodiments, the polyoxyl stearoyl glyceride is Gelucire® 50/13.

[0037] Pharmaceutical formulations contain about 3 to about 15% (w/w), based on the weight of the formulation, of polyoxyl stearoyl glyceride. In some embodiments, the pharmaceutical formulations contain 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), of the polyoxyl stearoyl glyceride. In other embodiments, the pharmaceutical formulations contain 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) of polyoxyl stearoyl glyceride. In other embodiments, the pharmaceutical formulations contain about 7% (w/w) of polyoxyl stearoyl glyceride.

[0038] The pharmaceutical formulation also contains a non-ionic poly (ethylene oxide) polymer. The term "non-ionic poly(ethylene oxide)" as used herein refers to a polymer with the following structure that is a liquid at room temperature. 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; 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; about 10,000 to about 20,000. In other embodiments, n is about 2,000; 3,000; 4,000; 5,000; 6,000; 7,000; 8,000; 9,000; 10,000; 15,000; 20,000; 25,000; 30,000; 35,000; 40,000; 45,000; 50,000; 55,000; 60,000; 65,000; 70,000; 75,000; 80,000; 85,000; 90,000, 95,000; or 100,000.

[0039] In some embodiments, the nonionic poly(ethylene oxide) polymer has a molecular weight (Mw) of about 400,000 to about 8,000,000. In other embodiments, the nonionic poly(ethylene oxide) has a Mw 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. In other embodiments, the nonionic poly(ethylene oxide) polymer has a Mw of about 500,000, about 600,000, about 700,000, about 800,000, about 900,000, about 1,000,000, about 2,000,000 , about 3,000,000, about 4,000,000, about 5,000,000, about 6,000,000, about 7,000,000 or about 8,000,000. In still other embodiments, the nonionic poly(ethylene oxide) has a Mw of about 7,000,000. In still other embodiments, the nonionic poly(ethylene oxide) is polyethylene oxide 303. In still other embodiments, the nonionic poly(ethylene oxide) is POLYOX™ WSR 303.

[0040] The nonionic poly(ethylene oxide) polymer is present in pharmaceutical formulations at about 5 to about 40% (w/w), based on the weight of the formulation. In some embodiments, the pharmaceutical formulations contain 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), about 5 to about 15% (w/w), 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 /wt), about 5 to about 30% (w/w), about 5 to about 25% (w/w), or about 5 to about 20% (w/w) of the polypolymer (ethylene oxide) non-ionic. In other embodiments, the pharmaceutical formulations contain about 12 to about 25% (w/w) of the nonionic poly(ethylene oxide) polymer. In other embodiments, the pharmaceutical formulations contain 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) of non-ionic poly(ethylene oxide) polymer. In other embodiments, the pharmaceutical formulations contain about 19% (w/w) of nonionic poly(ethylene oxide) polymer.

[0041] The pharmaceutical formulations also contain a medium chain triglyceride as defined above. In some embodiments, the fatty acid moiety has an aliphatic tail of about 6, 7, 8, 9, 10, 11, or 12 carbon atoms. In other embodiments, the medium chain triglyceride is caproic acid. In other embodiments, the medium chain triglyceride is caprylic acid. In still other embodiments, the medium chain triglyceride is capric acid. In still other embodiments, the medium chain triglyceride is lauric acid.

[0042] Medium chain triglyceride is 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 formulations contain 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 the medium chain triglyceride. In some embodiments, the pharmaceutical formulations contain about 50 to about 68% (w/w) of the medium chain triglyceride. In other embodiments, the pharmaceutical formulations contain 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) of the medium chain triglyceride. In still other embodiments, the pharmaceutical formulations contain about 64% (w/w) of the medium chain triglyceride.

[0043] In some aspects, pharmaceutical formulations contain about 1 to about 20% (w/w), based on the weight of the formulation, of domperidone or a pharmaceutically acceptable salt thereof, about 3 to about 15%. (w/w) polyoxyl stearoyl glyceride, about 5 to about 40% (w/w) nonionic poly(ethylene oxide) polymer, and about 40 to about 80% (w/w) triglyceride medium chain. In some aspects, the pharmaceutical formulations contain about 1 to about 10% (w/w), based on the weight of the formulation, of domperidone or a pharmaceutically acceptable salt thereof, about 3 to about 10% (w/w). p) polyoxyl stearoyl glyceride, about 5 to about 25% (w/w) of the non-ionic poly(ethylene oxide) polymer and about 40 to about 68% (w/w) of the medium chain triglyceride .

[0044] Domperidone formulation containing a nonionic poly(ethylene oxide) polymer and polyethylene glycol

[0045] In other embodiments, the present disclosure provides pharmaceutical formulations comprising domperidone or a pharmaceutically acceptable salt thereof, a nonionic poly(ethylene oxide) polymer, and a polyethylene glycol.

[0046] As a component, pharmaceutical formulations contain a non-ionic poly (ethylene oxide) polymer as defined above. In some embodiments, the nonionic poly(ethylene oxide) is polyethylene oxide 303. In other embodiments, the nonionic poly(ethylene oxide) is POLYOX™ WSR 303.

[0047] The nonionic poly(ethylene oxide) polymer is present in pharmaceutical formulations at about 5 to about 30% (w/w), based on the weight of the formulation. In some embodiments, the pharmaceutical formulations contain 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 from 5 to about 20% (w/w) of the nonionic poly(ethylene oxide) polymer. In other embodiments, the pharmaceutical formulations contain about 10 to about 20% (w/w) of the non-ionic poly(ethylene oxide) polymer. In other embodiments, the pharmaceutical formulations contain 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) of the nonionic poly(ethylene oxide) polymer. In still other embodiments, the pharmaceutical formulations contain about 15% (w/w) of the non-ionic poly(ethylene oxide) polymer.

[0048] Pharmaceutical formulations also contain polyethylene glycol. The term "polyethylene glycol" as used herein refers to a chemical compound with the following structure, which is a liquid at room temperature, where m is about 7 to about 20. 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 m is about 8 to 9. In other embodiments, m is about 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, or about 20. In still other embodiments, m is about 8. In still other embodiments, m is about 9. Polyethylene glycol also has a molecular weight (Mw) of about 300 to about 1,000. In some embodiments, the polyethylene glycol has a Mw 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. In other embodiments, the polyethylene glycol has a Mw of about 400, about 450, about 500, about 550, about 00, about 650, about 700, about 750, about 800, about 850 , about 900, about 950 or about 1,000. In still other embodiments, the polyethylene glycol has a Mw of about 400. In still other embodiments, the polyethylene glycol is polyethylene glycol 400.

[0049] Pharmaceutical formulations contain about 70 to about 90% (w/w), based on the weight of the formulation, of polyethylene glycol. In some embodiments, the pharmaceutical formulations contain 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 formulations contain 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). In other embodiments, the pharmaceutical formulations contain about 75% (w/w) of polyethylene glycol.

[0050] In some aspects, pharmaceutical formulations contain about 1 to about 20% (w/w), based on the weight of the formulation, of domperidone or a pharmaceutically acceptable salt thereof, about 5 to about 30%. (w/w) of nonionic poly(ethylene oxide) polymer and about 70 to about 90% (w/w) of polyethylene glycol. In other aspects, the pharmaceutical formulations contain about 1 to about 10% (w/w), based on the weight of the formulation, of domperidone or a pharmaceutically acceptable salt thereof, about 5 to about 20% (w/w). p) of the nonionic poly(ethylene oxide) polymer and about 70 to about 80% (w/w) of polyethylene glycol.

[0051] The pharmaceutical formulations described in this document may also contain one or more antioxidants. In some embodiments, the pharmaceutical formulations contain an antioxidant. In other embodiments, the pharmaceutical formulations contain two antioxidants. In other embodiments, the pharmaceutical formulations contain three antioxidants. The antioxidant can be selected by those skilled 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 other embodiments, the antioxidant is BHA. In other embodiments, the antioxidant is BHT. In still other embodiments, the antioxidant is BHA and BHT.

[0052] The total amount of antioxidant in the pharmaceutical formulation is about 0.01 to about 0.5% (w/w) of the total weight of the formulation. In some embodiments, the amount of one or more antioxidants in the pharmaceutical formulation is from 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, about 0.05 to about 0.1% (w/w). In other embodiments, the pharmaceutical formulations contain 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 other embodiments, the pharmaceutical formulations contain about 0.1% (w/w) of the antioxidant. In still other embodiments, the pharmaceutical formulations contain about 0.05% (w/w) of the antioxidant. In still other embodiments, the pharmaceutical formulations contain about 0.15% (w/w) of the antioxidant. In other embodiments, the pharmaceutical formulations contain about 0.1% (w/w) BHA. In other embodiments, the pharmaceutical formulations contain about 0.05% (w/w) BHT. In still other embodiments, the pharmaceutical formulations contain about 0.1% (w/w) BHA and 0.05% (w/w) BHT.

[0053] The domperidone formulations described herein are useful in a variety of treatment methods, including, without limitation, methods for treating a disorder that is gastroparesis, nausea other than gastroparesis, vomiting other than gastroparesis, nausea associated with gastroparesis , vomiting associated with gastroparesis, gastroesophageal reflux disease, insufficient lactation, nausea and/or vomiting associated with chemotherapy or a combination thereof. The methods include administering to the 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 in addition to gastroparesis. In other embodiments, the methods are useful for treating vomiting in addition to 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 other embodiments, the methods are useful for treating insufficient lactation. In still other embodiments, the methods are useful for treating nausea and/or vomiting associated with chemotherapy.

[0054] Pharmaceutical formulations can be administered by any acceptable route. In some embodiments, administration of the pharmaceutical formulations is oral, transdermal, parenteral, or a combination thereof. In other modalities, administration is oral.

[0055] Pharmaceutical formulations can be formulated for administration in solid or liquid forms. In some embodiments, the pharmaceutical formulations are formulated in the form of a tablet, caplet, capsule, powder, soft gel capsule, suspension or liquid, or a combination thereof. In other embodiments, the pharmaceutical formulations are formulated in the format of a tablet. In other embodiments, the pharmaceutical formulations are formulated in the shape of an oblong tablet. In still other embodiments, the pharmaceutical formulations are formulated in the format of a capsule. In still other embodiments, the pharmaceutical formulations are formulated in the form of a powder. In other embodiments, the pharmaceutical formulations are formulated in the format of a soft gel capsule. In other embodiments, the pharmaceutical formulations are formulated in suspension format. In still other embodiments, the pharmaceutical formulations are formulated in the format of a liquid.

[0056] The following examples are provided to illustrate some of the concepts described in this disclosure. Although each Example is intended to provide specific individual embodiments of formulations, methods of preparation and use, none of the Examples should be considered to limit the more general embodiments described herein.

[0057] In the following examples, efforts have been made to ensure accuracy with respect to the numbers used (e.g. quantities, temperature, etc.), but some experimental errors and deviations must be taken into account. Unless otherwise stated, temperature is in degrees C; Cmax = maximum plasma concentration; tmax = time of maximum plasma concentration; MRTlast = average residence time, calculated up to the last observable time point; AUClast = area under the curve, calculated up to the last observable time point.

EXAMPLES Example 1: Formulation Preparation

[0058] Five formulations, that is, AE, containing domperidone were prepared by combining the components identified in Table 1.

[0059] Formulations A-C and E were formulated as liquids or semisolids and placed in capsules and formulation D was compressed to form a tablet using a single-station notching press.

Example 2

[0060] Pharmaceutical formulations of Domperidone are prepared and encapsulated in a GMP encapsulation machine using the values observed in Tables 2-4. Specifically, compounding activities are conducted under a blanket of nitrogen and yellow light. The batches are then encapsulated using the 2C oval die and single bottom shot wedge with 0.040" bore at a temperature of about 38.7 to 51.7°C. Capsules are hand polished with a medium chain triglyceride/lecithin blend (97% MCT/3% lecithin).

[0061] It should be understood that although the invention has been described in conjunction with its specific preferred embodiments, the foregoing description and the examples that follow are intended to illustrate and not limit the scope of the invention. It will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the scope of the invention, and further that other aspects, advantages and modifications will be apparent to those skilled in the art to which the invention belongs. In addition to the embodiments described in this document, the present invention contemplates and claims those inventions resulting from the combination of characteristics of the invention cited in this document and those of the cited prior art references that complement the characteristics of the present invention. Likewise, it will be appreciated that any material, resource or article described may be used in combination with any other material, resource or article, and such combinations are considered to be within the scope of this invention.

[0062] The disclosures of each patent, patent application and publication cited or described in this document are incorporated herein by reference, each in its entirety, for all purposes.

Claims (17)

1. Pharmaceutical formulation, characterized by the fact that it comprises: (i) domperidone or a pharmaceutically acceptable salt thereof; a glyceryl stearate and a medium chain triglyceride or (ii) domperidone or a pharmaceutically acceptable salt thereof; a polyoxyl stearoyl glyceride, a nonionic poly(ethylene oxide) polymer and a medium chain triglyceride or (iii) domperidone or a pharmaceutically acceptable salt thereof, a nonionic poly(ethylene oxide) polymer and a polyethylene glycol . 2. Pharmaceutical formulation according to claim 1, characterized in that it comprises domperidone or a pharmaceutically acceptable salt thereof, a glyceryl stearate and a medium chain triglyceride. 3. Pharmaceutical formulation according to claim 1 or 2, characterized in that the glyceryl stearate is a glyceryl palmitostearate, a glycerol distearate, a glyceryl distearate or a combination thereof. 4. Pharmaceutical formulation according to any one of the preceding claims, characterized in that it comprises from 2 to 20% (w/w), based on the weight of the formulation, of glyceryl stearate, preferably from 5 to 15% ( w/w), or more preferably 10% (w/w). 5. Pharmaceutical formulation according to any one of the preceding claims, characterized by the fact that it comprises from 70 to 90% (w/w), based on the weight of the formulation, of medium chain triglyceride, or preferably from 80 to 85 % (w/w). 6. Pharmaceutical formulation, according to any of the previous claims, characterized by the fact that the glyceryl stearate is Precirol® ATO 5. 7. Pharmaceutical formulation according to claim 1, characterized in that it comprises domperidone or a pharmaceutically acceptable salt thereof, a polyoxyl stearoyl glyceride, a nonionic poly(ethylene oxide) polymer and a medium chain triglyceride . 8. Pharmaceutical formulation according to claim 1, characterized in that it comprises domperidone or a pharmaceutically acceptable salt thereof, a nonionic poly(ethylene oxide) polymer and a polyethylene glycol. 9. Pharmaceutical formulation according to any of the preceding claims, characterized in that it further comprises an antioxidant. 10. Pharmaceutical formulation according to claim 9, characterized by the fact that 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. 11. Pharmaceutical formulation according to any one of the preceding claims, characterized by the fact that it comprises from 1 to 20% (w/w), based on the weight of the formulation, of domperidone, preferably from 5 to 12% (w/w). p), or more preferably 10% (w/w). 12. Pharmaceutical formulation according to any of the preceding claims, characterized in that it comprises from 1 to 50 mg of domperidone. 13. Use of the formulation defined in any one of claims 1 to 12 characterized in that it is in the preparation of a medicament to treat a disorder 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 in a patient in need thereof comprising administration to the patient of said formulation. 14. Use according to claim 13, characterized in that the formulation is in the form of a tablet, capsule, soft gel capsule, suspension, liquid or combination thereof. 15. Use according to claim 13, characterized by the fact that the disorder is gastroparesis. 16. Use according to claim 13, characterized by the fact that the disorder is gastroesophageal reflux disease. 17. Use according to claim 13, characterized by the fact that the disorder is insufficient lactation.