EA045546B1 - METHOD FOR RELIEFING DISEASE OR CONDITION ASSOCIATED WITH GASTROINTESTINAL TRACT MOTORISM USING DEUTERATED DOMPERIDONE - Google Patents

Description

Cross reference to related applications

This invention claims priority to U.S. Patent Application No. 15/639,431, filed June 30, 2017, the disclosure of which is incorporated by reference in its entirety.

Prerequisites for creating the invention

Gastroparesis (GP) is a condition in which the motility of the stomach does not function or does not function properly, preventing gastric emptying and impairing digestion.

GP may be caused by damage to the vagus nerve, which regulates digestion. Damage to the vagus nerve can be caused by diseases such as type I or type II diabetes, or surgery on the stomach or small intestine, and can limit the nervous system's ability to send signals to the stomach muscles. Viral infections, certain medications, certain cancer treatments, scleroderma, nervous system disorders such as Parkinson's disease or multiple sclerosis, or hypothyroidism may also cause or lead to GP.

GP is typically diagnosed using upper gastrointestinal (GI) endoscopy, computed tomography (CT), enterography, magnetic resonance enterography, upper GI x-ray (x-ray), gastric emptying study, and/or a breath test. Symptoms of GP include nausea, vomiting, changes in blood glucose levels, abdominal pain, bloating, feeling full after eating a few bites of food, lack of appetite, weight loss and malnutrition. Untreated GP can lead to severe dehydration, nutritional deficiencies, solidification of undigested food in the stomach (bezoar), and abnormal changes in blood glucose levels, which can worsen diabetes.

Treatment of GP involves identification and treatment of the underlying pathology. GP resulting from diabetes can be treated by changing diet. GP can be treated with drugs to stimulate the stomach muscles, such as metoclopramide, erythromycin, and cisapride. Metoclopramide has serious side effects, such as movement disorders, or may interact unfavorably with other medications; erythromycin may lose effectiveness as the patient becomes accustomed to this drug; and cisapride has limited availability. Medicines to control nausea and vomiting include prochlorperazine, thiethylperazine, diphenhydramine, and ondansetron.

Symptoms of GP can be treated with surgery, such as insertion of a jejunostomy tube into the small intestine or insertion of a gastric ventilation catheter. In severe cases, a feeding tube may be inserted orally or nasally for direct placement into the small intestine, or administered parenterally.

Domperidone is an effective dopamine antagonist that does not readily cross the blood-brain barrier; thus, domperidone exhibits only minimal extrapyramidal side effects. Domperidone exhibits both gastrokinetic and antiemetic activity and exerts its gastrokinetic effect by acting on peripheral dopamine receptors in the stomach. Domperidone acts as a peripherally selective dopamine D2 and D3 receptor antagonist, and its action is aimed at blocking the dopamine receptors that register nausea. Domperidone can block dopamine receptors in the pyloric cave and duodenum to increase motility in the upper gastrointestinal tract. Domperidone can also block dopamine receptors in the pituitary gland, which can increase the release of prolactin, leading to increased lactation, so it is used to treat hypogalactia. Domperidone has been evaluated for use in the treatment of nausea and vomiting, gastroparesis, Parkinson's disease, functional dyspepsia, hypogalactia, infantile reflux, gastroesophageal reflux disease, and other GI motility disorders or conditions.

The essence of the invention

In some embodiments, the present invention provides therapeutic methods for alleviating any or all of the following disorders: gastroparesis, nausea as a disorder independent of or associated with gastroparesis, vomiting as a disorder independent of or associated with gastroparesis, gastroesophageal reflux disease (GERD) , functional dyspepsia, chemotherapy-associated nausea and vomiting, and/or hypogalactia, by administering domperidone deuterated with four deuterium atoms on the non-chlorinated aromatic ring (d ₄ ) or six deuterium atoms on the linking propyl group (d ₆ ). In one embodiment, domperidone-d ₄ is administered and is preferred over domperidone-d ₆ .

In other embodiments, the present invention provides methods for alleviating gastroesophageal reflux disease, functional dyspepsia, or chemotherapy-associated nausea and vomiting in a patient, comprising administering to the patient a therapeutically effective amount of a compound that is d ₂ -domperidone 4, d ₄ -domperidone 2, d ₆ -domperidone 3 or d ₁₀ -domperidone 5, or a pharmaceutically acceptable salt thereof:

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(a ₄ -domperidone) (a ₁₀ -domperidone).

In some aspects, the compound is d ₄ -domperidone.

In other embodiments, the present invention provides methods for producing deuterated domperidone. In some aspects, the methods include reacting a 1,2-diaminobenzene containing 0-4 deuterium atoms with a reactive carbonyl group to produce a cyclic imide, reacting a cyclic imide with a protecting group to produce a monoprotected cyclic imide, reacting a monoprotected cyclic imide with a 1,3-bifunctional propyl derivative containing 0-6 deuterium atoms to obtain an intermediate, reacting the intermediate with 5-chloro-1-(4-piperidinyl)1,3-dihydro-2H-benzimidazol-2-one and removing the protecting group to either, or after reacting the intermediate with 5-chloro-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one.

In other embodiments, the present invention provides a compound of Formula 16 wherein R=H or D:

which

In other embodiments, the present invention provides a compound that is 1-(3-chloropropyl-1,1,2,2,3,3- _d6 )-4,5,6,7-tetradeutero-2-ethoxybenzimidαzole:

which

In other embodiments, the present invention provides a connection that is:

which

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Brief description of drawings

Fig. 1A, 1B show the plasma profile of orally administered domperidone and deuterated domperidone (FIG. 1A) and analysis of the data shown in FIG. 1A (Fig. 1B).

Fig. 2 shows a representative drug release profile for an immediate release (IR) formulation and an extended release (XR) formulation.

Fig. 3 shows the simulated plasma profile of deuterated domperidone from an immediate release portion and an extended release portion.

Fig. 4 shows a two-layer tablet with IR and ER layers.

Fig. 5 shows a three-layer tablet containing IR, ER and a buffer layer.

Fig. 6 shows a tablet with ER matrix and IR coating.

Fig. 7 shows a capsule containing an IR tablet, a stopper and an ER tablet with an osmotic system.

Fig. 8 shows a capsule containing IR and ER spherical particles.

Fig. 9 shows a capsule containing IR and ER mini-tablets.

Fig. 10 shows a capsule containing IR and ER granules.

Fig. 11 shows a capsule containing an ER sphere coated with a TR layer.

Fig. 12 shows a compressed tablet containing IR granules and an ER coated tablet contained within the compressed tablet.

Fig. 13 shows a compressed IR tablet with an ER tablet enclosed within an IR tablet.

Fig. 14 shows an ER tablet suspended in IR liquid.

Fig. 15 shows a sachet containing a mixture of IR and ER granules or spherical particles.

Fig. 16 shows a sachet containing effervescent IR beads or spheres and coated ER beads or spheres.

Fig. 17 shows a tablet with interlayers separated by stripes.

Fig. 18 shows an orally disintegrating tablet containing coated sustained release/ER drug particles, spheres or granules; inset shows drug in polymer matrix.

Fig. 19 shows a capsule containing a drug solution and sustained release/ER drug coated particles, spheres or granules.

Fig. 20 shows a soft gelatin capsule containing a drug solution and sustained release/ER drug coated particles, spheres or granules.

Fig. 21 shows a liquid carrier containing coated sustained release/ER drug particles, spheres or granules.

Fig. 22A, 22B are line graphs showing the effect of domperidone or d4-domperidone suspensions on _Cmax and AUC, respectively.

Detailed Description of the Invention

In the present disclosure, singular forms also include plural forms, and reference to a specific numerical value includes at least that specific value unless the context clearly indicates otherwise. Thus, for example, reference to a substance means reference to at least one of such substances and their equivalents known to those skilled in the art, etc.

When a value is expressed as an approximation using the word about, it should be understood that the particular value constitutes another embodiment. In general, the use of the term about indicates approximations that may vary depending on the desired properties to be achieved by the disclosed subject matter, and must be interpreted in the particular context in which it is used based on its function. One skilled in the art may interpret this as actions carried out in the usual manner. In some cases, the number of significant figures used for a particular meaning may be one non-limiting way of determining the scope of a word about. In other cases, the gradations used in a range of values may be used to determine the expected range to be assigned to the term about for each value. When present, all ranges are inclusive and combinable. That is, references to values specified in ranges include every value in that range.

When a list is presented, unless otherwise indicated, it is understood that each individual element of this list and each combination of this list is to be interpreted as a separate embodiment. For example, a listing of embodiments represented as A, B, or C should be interpreted to include embodiments A, B, C, A or B, A or C, B or C, or A, B, or C.

It should be understood that certain features of the invention, which for clarity are described in the context of individual embodiments of the present invention, may also be presented in combination in a single embodiment. That is, unless clearly incompatible or excluded, it is intended that each individual embodiment may be combined with any other embodiment(s), and such combination is considered another embodiment. Conversely, various features of the invention, which for brevity are described in the context of a single embodiment, may also be provided separately or in any combination. In addition, it should be noted that the claims may be drafted in such a way as to exclude an optional element. As such, this statement is intended to serve as a precursor to the use of exclusionary terminology such as exclusively, solely, etc., in connection with the enumeration of claimed elements or the use of a negative limitation. Finally, although an embodiment may be described as part of a sequence of steps or part of a more general structure, each said step may itself also be considered an embodiment in its own right.

Unless otherwise stated herein, percentages refer to weight/volume.

The terms subject and patient are used interchangeably and generally refer to mammals. In some embodiments, the patient or subject is a human. In other embodiments, the patient or subject is a veterinary animal being treated or a farm animal, domestic animal or pet, or an animal used for clinical research.

The term alleviation or variations thereof means eliminating or reducing the progression of a disease or disorder, i.e. delay in onset of the disease. In other embodiments, treatment refers to eliminating or reducing at least one physical parameter of the disease or disorder.

Domperidone as used herein refers to 5-chloro-1-(1-[3-(2-oxo-2,3-dihydro1H-benzo[d]imidazol-1-yl)propyl]piperidin-4-yl) -1H-benzo[d]imidazol-2(3H)-one, which has the following structure:

Any reference to domperidone also includes pharmaceutically acceptable salts, esters, hydrates, solvates, prodrugs and derivatives thereof, which are broadly defined as domperidone compounds that are modified or partially substituted, examples including, but not limited to, single atom addition, addition reactive group, addition of a functional group, formation of a dimer or multimer, conjugation with another molecule such as an antibody, etc.

Pharmaceutically acceptable refers to properties and/or substances that are acceptable to the patient from a pharmacological/toxicological point of view, and to the production of a pharmaceutical preparation that is advantageous from a physical/chemical point of view with regard to composition, dosage form, stability, patient acceptability and bioavailability .

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

The abbreviation D as used herein refers to the stable isotope of hydrogen, which is deuterium (heavy hydrogen or ^2H ). Such D cases involve amounts of deuterium that are higher than the natural distribution of deuterium. In some embodiments, D has a deuterium enrichment of no less than about 1%. In other embodiments, D has a deuterium enrichment of no less than about 5%. In other embodiments, D has a deuterium enrichment of no less than about 10%. In other embodiments, D has a deuterium enrichment of no less than about 20%. In other embodiments, D has a deuterium enrichment of no less than about 30%. In other embodiments, D has a deuterium enrichment of no less than about 40%. In yet other embodiments, D has a deuterium enrichment of no less than about 50%. In other embodiments, D has a deuterium enrichment of no less than about 60%. In other embodiments, D has a deuterium enrichment of no less than about 70%. In other embodiments, D has a deuterium enrichment of no less than about 80%. In some other embodiments, D has a deuterium enrichment of at least about 90%. And in still some embodiments, D has deuterium enrichment of at least about 98% deuterium. And in still some embodiments, D has deuterium enrichment of at least about 99% deuterium. And in still some embodiments, D has deuterium enrichment of at least 99% deuterium.

As with all drugs, the safety of domperidone depends on its metabolism. Reduced metabolism leads to a longer presence of the drug in the body. Doses of domperidone required to treat gastroparesis, i.e. 10 mg administered three times daily, for a total of 30 mg, and up to 60 mg, may result in QT prolongation in a dose-dependent manner. Because of this effect, it is not approved for this indication in the United States, but is approved in Europe and Canada.

Domperidone is extensively metabolized; its major metabolic pathways produce the 5-hydroxy form, the N-dealkylated form, and the hydroxylated form. Thus, methods that reduce the metabolism of domperidone will allow a lower dose to be administered to achieve the same degree of efficacy in the patient, reducing or eliminating the cardiac effect, and/or reducing the number of doses required to administer, and/or providing a more consistent exposure, which may increase patient tolerability or effectiveness.

Overall peak plasma levels of domperidone depend on the route of administration. Intramuscular (IM) and oral administration to a fasting patient resulted in peak plasma levels at 10 and 30 min after administration; administration of the suppository resulted in peak plasma levels 1 to 2 hours after administration. Plasma concentrations were lower two hours after oral administration compared with intramuscular administration, likely due to first pass in the liver and mural metabolism in the intestine. Peak plasma concentrations were 40 ng/mL following a 10 mg IM injection, 20 ng/mL following oral administration of a 10 mg tablet, and 70–100 ng/mL following oral administration of a 60 mg tablet or drops. The binding to human plasma proteins at a dose of 10 and 100 ng/ml of tritiated domperidone was 91.7 and 93.0%, respectively. Bioavailability was relatively high at 90% after IM injection and relatively low at 13-17% after oral administration and was even further reduced with the use of an antacid due to increased gastric pH. RxMed: Pharmaceutical Information - MOTILIUM®, Janssen-Ortho, Domperidone Maleate.

Compared to tritiated spiperone, a classic ligand used in central nervous system (CNS) models, domperidone binds selectively and specifically to striatal dopamine receptors. However, intravenous (IV) administration of domperidone, even at high doses, does not replace labeled spiperone in animal models of the brain due to its poor penetration of the blood-brain barrier (Reddymasu et al., Am. J. Gastroenterology). Domperidone also has a high affinity for GI tissue; High concentrations are found in the esophagus, stomach and small intestine. Domperidone blocks dopaminergic inhibition of GI transit. It is rapidly metabolized in the liver; after oral administration, 32% is excreted in urine and 66% is excreted in feces. The half-life is 7.5 hours in healthy subjects and approximately three times longer in subjects with renal dysfunction.

The effectiveness of domperidone is based on its ability to increase the amplitude of esophageal motor function, enhance antroduodenal contractions and better coordinate peristalsis through the pylorus with subsequent acceleration of gastric emptying. Domperidone has effective antiemetic activity at the chemoreceptor trigger zone (CTZ) in the fourth ventricle of the brain, but outside the blood-brain barrier. It has no cholinergic activity and is not inhibited by atropine.

Domperidone modulates gastric emptying of both solids and liquids and does not alter gastric acid secretion, secretory volume, intragastric pH, or serum gastrin concentration.

At doses ranging from 10 to 30 mg, orally four times daily 0.5 hours before meals and at bedtime, domperidone significantly reduced gastrointestinal symptoms and hospitalizations due to gastroparesis, had a positive effect on central control of vomiting and nausea, and accelerated elimination of solid foods (Buckels et al., Medscape General Medicine. 2003; 5(4), www.medscape.com).

One way to reduce the metabolism of domperidone is to administer a deuterated form of domperidone. Domperidone is extensively metabolized. Deuteration slows down metabolism at key metabolic sites and pathways, providing greater potency at a lower dose. The deuterated form of the small molecule increases its retention and thus reduces its metabolism, allowing a lower dose to be administered while achieving the same efficacy as a higher dose without cardiac symptoms.

Deuterated domperidone can be synthesized or produced in several ways. Generally, any hydrogen in the chemical structure of domperidone can be either hydrogen or deuterium. Preferred sites of domperidone metabolism, i.e. all unsubstituted sites on the aromatic rings can be blocked by adding a commercially available deuterated alkyl halide, and the metabolite can be blocked by adding a commercially available deuterated alkyl halide for the propyl linker. This can significantly reduce the metabolism of domperidone and improve its bioavailability.

Deuteration of a drug increases the half-life of the drug, which allows for less frequent dosing, and also improves pharmacokinetics, i.e. absorption, distribution and metabolism. Kinetic isotope effect (KIE) and deuterium kinetic isotope effect (DKIE) are used to incorporate deuterium into drugs. Gant, J. Med. Chem. (2014), 57, 3595-3611.

Deuterium forms more stable bonds with carbon than hydrogen. In some cases, substitution with deuterium may result in altered drug metabolism. Altered drug metabolism can take various forms, such as improved metabolite stability, reduced formation of toxic metabolites, and/or increased formation of active metabolites. Deuterated compounds may have a longer half-life and increased systemic exposure compared to the corresponding non-deuterated forms. The longer half-life and reduced metabolism may provide increased efficacy, tolerability, safety and convenience, so lower doses of the deuterated form may produce the same results as higher doses of the non-deuterated form. Deuterated compounds generally retain the same biochemical activity and selectivity as the corresponding non-deuterated forms. Any effects of deuterium substitution on metabolic parameters are highly dependent on the specific molecular positions at which deuterium replaces hydrogen.

The metabolic effects of deuterium substitution are not obvious or predictable, even in compounds that have similar chemical structures. For example, US Publication No. 2009/0076010 discloses deuterium-enriched lamotrigine, an anticonvulsant. Deuteration ranges from 14 to 100%, depending on the position of the hydrogen replaced by deuterium. Enrichment methods may include proton exchange with deuterium or synthesis of molecules with deuterium-enriched starting materials. US Publication No. 2009/0131485 discloses deuterium-enriched pirfenidone, an inhibitor of collagen production that blocks proliferation and stimulation of fibroblasts in response to cytokines, investigated for the treatment of neurofibromatosis, multiple sclerosis and other fibrotic diseases. It discloses synthesis methods and isotopes, as well as methods for increasing bioavailability and dosing. Deuterated pirfenidone has a half-life of 110 to 140% or more, depending on the degree of deuteration. The effective amount is 80 to 40% or less compared to non-deuterated forms. US Publication No. 2011/0160253 discloses deuterium-enriched tizanidine, a benzothiazole compound that acts as a centrally acting _α2- adrenergic receptor agonist used to treat muscular hypertension and muscle spasticity associated with multiple sclerosis, spinal cord injury, etc. She reveals deuteration methods; the fortification range is from 52.5 to 99.5%, and pharmaceutical compositions, effective amounts and doses are disclosed. Harbeson and Tung, MECHEM NEWS, No. 2, May 2014, 8-22 disclose that substitution with deuterium can improve the safety, efficacy and/or tolerability of a therapeutic agent.

Deuterated drugs are used in nonclinical settings and as metabolic and pharmacokinetic probes, but none are approved as therapeutic agents for humans. Depending on the desired deuteration sites, D2O can be used as a substitute directly in finished drug compounds or in reagents used for drug synthesis. Deuterium has low systemic toxicity. Deuterium gas can be used as a starting material for deuterium incorporation. Catalytic deuteration of olefin and acetylene bonds can quickly involve deuterium. Metal catalysts such as Pd, Pt and Rh, in the presence of deuterium gas, can be used to directly replace hydrogen with deuterium in hydrocarbon-containing functional groups. Deuterated reagents and synthetic building blocks are commercially available. The shape and size of the molecule are very similar in deuterated and non-deuterated forms. Minor changes in physical properties in partially or fully deuterated compounds include decreased hydrophobicity, decreased acidity of carboxylic acids and phenols, and increased basicity of amines, but most of these small differences have negligible effects on biochemical activity or target selectivity. Binding isotope effects are well known and can make positive or negative contributions to the measured deuterium kinetic isotope effect. Metabolic rates and metabolic switches, where the ratio of metabolites changes, also decrease. Changes in an individual's exposure to the parent drug and metabolites may affect the pharmacodynamics, tolerability, and efficacy of the deuterated drug. Deuteration reduces the formation of unwanted or toxic metabolites and also increases the formation of desired metabolites. An example of the beneficial effects of metabolic switching is deuterated nevirapine, which resulted in a reduction in the incidence and severity of scabies, and deuterated efavirenz, indilone, and odanacatib each resulted in reduced side effects with increased efficacy in

- 6 045546 rat model. Deuterated rofecoxib, also known as BDD-11602, had an improved pharmacokinetic profile in a rat model compared to non-deuterated rofecoxib. Deuterated telaprevir, an inhibitor of hepatitis C virus NS3-4A protease, had a 13% increase in epimerization rate but little effect on antiviral activity. The effects of deuteration on the metabolic profile of any particular drug are not predictable, although there is potential to improve safety, tolerability, efficacy and dosing.

One method of reducing the metabolism of domperidone involves administering a deuterated form of domperidone. The deuterated form of a small molecule can increase its retention time and thus reduce its metabolism, allowing a lower dose to be administered with the same efficacy as a higher dose but without cardiac symptoms. Domperidone is extensively metabolized, but deuteration slows metabolism at key sites and key metabolic pathways, providing greater potency at a lower dose. This is shown in Fig. 1A and 1B, described below, where the area under the curve is greater for deuterated compounds. The table described below shows the reduction in metabolite formation for Compound 2 over a 60 min time period.

Compound 1 below shows the general deuterated form of domperidone, where R=H or D, independently, allowing the presence of 1 to 10 deuterium atoms. Any permutation of deuterated sites can be used without restrictions. The most significant sites of deuteration are the aromatic hydrocarbon groups, as shown, and the alkyl linker methylene alpha relative to the piperidine nitrogen. Primary hydroxylated metabolites are present on this aromatic ring, and the presence of deuterium can reduce the rate of formation of these metabolites. The dealkylation metabolic pathway involves these alpha protons through an N-oxide elimination mechanism; deuterium is removed more slowly, thus slowing down this metabolic pathway. In one embodiment, deuterated compounds 1 are used and/or prepared as described herein.

Domperidone can be deuterated at any hydrogen position. In compound 2, deuteration of the aromatic H atoms of the unsubstituted aromatic ring gives domperidone-d ₄ . Additional deuteration of one or more methylene sites in the linking propyl group gives compound 3 (domperidone-d ₆ ) or domperidone-d ₈ (not shown) or compound 5 (domperidone-d ₁₀ ). It is also possible to deuterate one or more methylene sites while retaining H at the aromatic sites. For example, deuteration of one methylene group gives compound 4 (domperidone-d ₂ ), and deuteration of two methylene groups gives domperidone-d ₄ (not shown).

In one embodiment, any of compounds 2, 3, 4, 5 or 6 is administered. Any of compounds 2, 3 and 4 act to reduce the metabolic rate and are preferred.

Precursors with only alpha methylene deuterium are likely to be more expensive and less available than those where the propyl group is fully deuterated.

Compound 2 is used and preferred in one embodiment.

Compound 3 is used and preferred in another embodiment.

Compound 4 is used and preferred in another embodiment.

Compound 5 is used and preferred in one embodiment.

Compound 6 is used and preferred in yet another embodiment.

Compounds 2 and 5 are used and preferred in one embodiment.

Connections 2, 5 and 6 are used in one embodiment.

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In one embodiment, compounds containing 1-8 deuterium atoms in cyclohexylamine are used, such as compound 13:

Thus, the present invention provides methods for alleviating gastroesophageal reflux disease, functional dyspepsia, or chemotherapy-associated nausea and vomiting in a patient, comprising administering to the patient a therapeutically effective amount of a compound that is b ₂ -domperidone 4, b ₄ -domperidone 2, b ₆ -domperidone 3 or ₁₀ -domperidone 5, or a pharmaceutically acceptable salt thereof:

(yoyu-domperidone).

In some embodiments, the compound is b ₂ -domperidone 4 or a pharmaceutically acceptable salt thereof:

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In other embodiments, the compound is d ₄ -domperidone 2 or a pharmaceutically acceptable salt thereof:

(sC-domperidone).

In other embodiments, the compound is d ₆ -domperidone 3 or a pharmaceutically acceptable salt thereof:

(f-d omperidone).

In other embodiments, the compound is d ₁₀ -domperidone 5 or a pharmaceutically acceptable salt thereof:

(fo-domperidone).

In some embodiments, deuterated compounds can be used in the methods described herein to alleviate gastroesophageal reflux disease.

In other embodiments, deuterated compounds can be used in the methods described herein to alleviate functional dyspepsia.

In other embodiments, deuterated compounds can be used in the methods described herein to relieve nausea and vomiting associated with chemotherapy.

Scheme 1 shows the general synthesis for the preparation of various deuterated domperidone compounds, generally shown as compound 1. The synthesis is based on the non-deuterated analogue disclosed in US Pat. No. 4,066,772 to Vandenberk. The method begins with 1,2-diaminobenzene substituted with 0-4 deuterium atoms on the aromatic ring. The imide is capped using ethyl chloroformate or other similar reactive carbonyl compound in a suitable solvent such as, but not limited to, an ether such as tetrahydrofuran (THF), halohydrocarbons such as dichloromethane, ketones such as acetone, hydrocarbons such as heptane, and amides such as N,N-dimethylformamide (DMF). Compound 8 is then protected to form a monoprotected compound using a suitable protecting group such as, but not limited to, carbamates, sulfonamides and vinyl alkyls. The second nitrogen is then reacted with a 1,3-bifunctional propyl derivative containing 0-6 deuterium atoms. The functional group may be independently halogen (Br, Cl, I), hydroxyl, or a suitable leaving group such as tosylate or mesylate. In a preferred embodiment, the two groups are distinguished. The remaining leaving group X of compound 10 can optionally be exchanged for a more reactive group, for example, if X is a chloride, the chloride can be exchanged for iodide, or if X is a tosylate, the tosylate can be exchanged for trifluoromethanesulfonate (triflate). The protecting group P can also be removed at this stage.

Intermediate 10 or 12 is then reacted with compound 14 using either a base or other suitable coupling procedure. Compound 14 is prepared using methods known in the art. Removal of the protecting group provides the desired deuterated domperidone derivative 1. Alternatively, the protecting group P can be removed prior to alkylation with compound 14. All compounds are prepared according to this general scheme using suitably substituted deuterated starting materials.

The synthesis of compound 13 is carried out following known methods for non-deuterated substances, but starting from the deuterated 4-aminopiperidine derivative.

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Scheme 1

General synthesis of deuterated domperidone

Scheme 2 shows an alternative synthesis for deuterated domperidone. Suitably deuterated 1,2-aminobenzene is reacted with tetraethyl orthocarbonate in the presence of a catalyst and in a suitable solvent to produce compound 15. In one embodiment, the catalyst is acetic acid. In one embodiment, the solvent is ethanol. In another embodiment, the catalyst is propionic acid. In another embodiment, the solvent is isopropyl alcohol. In embodiments, a suitable organic or inorganic acid in a suitable solvent may be used, non-limiting examples include an ether or an alcohol. The 1,3-bifunctional propyl derivative containing 0-6 deuterium atoms is then reacted with the protonated nitrogen N of imide 15 in the presence of a base and in a solvent to produce compound 16. In one embodiment, the base is K ₂ CO ₃ . In one embodiment, the solvent is methyl isobutyl ketone (MIBK). In another embodiment, the base is sodium hydride. In another embodiment, the solvent is dimethylformamide (DMF). In embodiments, organic bases such as N,N-diisopropylethylamine (DIPEA), n-butyllithium (nBuLi), lithium bis-(trimethylsilyl)amide (LHMDS), etc., or inorganic bases can be used, as examples. , such as potassium hydride. Substitution with compound 14 and deprotection of the benzimidazole leads to deuterated domperidone 1.

Scheme 2

Synthesis of deuterated domperidone

Scheme 2, representing the synthesis of deuterated domperidone, includes only three steps, each of which leads to high yields of the product. The overall yield of deuterated domperidone from Scheme 2 is significantly higher compared to the yield of deuterated domperidone from Scheme 1.

In some embodiments, the present invention provides compounds of Formula 16 wherein R=H or D.

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In other embodiments, the present invention provides a compound wherein R=D in compound 16, i.e. the following connection:

In other embodiments, the present invention provides a compound of Formula 16 wherein R=H, i.e. connection of the following structure:

In some embodiments, methods are provided for preparing deuterated domperidone, Compound 1. The method comprises (i) reacting 1,2-diaminobenzene containing 0-4 deuterium atoms with tetraethyl orthocarbonate; (ii) reacting the product of step (i) with Br(CR ₂ ) ₃ Cl to obtain an intermediate; and (iii) reacting the intermediate with 5-chloro-1(4-piperidyl)-1 H-benzimidazole-2(3H)- onom.

In other embodiments, methods are provided for preparing deuterated domperidone, Compound 2. These methods include (i) reacting 1,2-diaminobenzene containing 4 deuterium atoms with tetraethyl orthocarbonate; (ii) reacting the product of step (i) with Br(CH ₂ ) ₃ Cl to obtain an intermediate and (iii) reacting the intermediate with 5-chloro-1-(4piperidyl)-1 H-benzimidazol-2(3H)-one .

Deuterated domperidone compounds may be administered by any route determined by one skilled in the art, including, but not limited to, oral, rectal, nasal, parenteral (i.e., subcutaneous, intradermal, intramuscular, intraperitoneal, intravenous, intraarticular, intramedullary), intraperitoneal, transmucosal , transdermal or topical (i.e. dermal, buccal, sublingual, intraocular). In some embodiments, the deuterated domperidone compounds are administered in the form of pharmaceutical compositions.

The compositions can be administered orally in solid form, such as a tablet, capsule, lozenge or chewing gum, or in liquid form as a syrup, emulsion, solution or suspension in an aqueous or non-aqueous vehicle. In solid forms, the compositions may be controlled-release or rapid dissolution for rapid onset of action. The compositions can also be administered by injection, which may be subcutaneous, intradermal, intramuscular, intravenous, or other injection routes. Compositions for injection may include suspensions, solutions or emulsions in aqueous or non-aqueous vehicles. Other compositions may be delivered intranasally, vaginally, rectally or transdermally. The compositions may also be delivered transmucosally. The drug can be administered one to four times a day.

Typically, pharmaceutical compositions are formulated to suit a particular route of administration. In some embodiments, the pharmaceutical compositions are in the form of tablets, capsules (hard and soft gelatin capsules), sachets, dragees, powders, granules, lozenges, reconstitution powders, liquid preparations (solutions, emulsions, suspensions or syrups),

- 11 045546 plasters, inhalations or suppositories. Thus, pharmaceutical compositions typically contain pharmaceutically acceptable excipients.

For inclusion in pharmaceutical compositions, pharmaceutically acceptable excipients are selected based on the route of administration and may include inert and/or active components. In some embodiments, the pharmaceutically acceptable excipient is sterile, non-toxic and/or biologically suitable for administration to a subject, i.e. buffered to suitable pH and isotonicity. In other embodiments, pharmaceutically acceptable excipients include diluents (eg, inerts), carrier, adjuvant, excipients.

Deuterated domperidone or a pharmaceutical composition including it may also contain other active substances and/or they can be administered with other active substances. In some embodiments, the additional active agent is useful for treating GERD. In other embodiments, the additional active agent is useful for treating functional dyspepsia. In other embodiments, the additional active agent is useful for treating nausea and/or vomiting associated with chemotherapy. Thus, additional active substance may include antacids, H2 blockers (such as cimetidine, famotidine, nizatidine or ranitidine), proton pump inhibitors (such as lansoprazole, omeprazole, pantoprazole, rabeprazole or dexlanzoprazole), drugs that strengthen the lower esophageal sphincter (eg, baclofen), anti-nausea or vomiting medications such as aprepitant, dolasetron, granisetron, ondansetron, palonosetron, proclorperazine, promethazine, netupitant-palonosetron, rolapitant, lorazepam, metoclopramide, or dexamethasone, or combinations thereof.

In some embodiments, deuterated domperidone is administered orally, transdermally, parenterally, or a combination of such routes of administration. In other embodiments, deuterated domperidone is administered transdermally. In other embodiments, deuterated domperidone is administered parenterally. In some other embodiments, deuterated domperidone is administered orally.

Fig. 1 shows the decrease in metabolism caused by deuteration of domperidone, where the area under the curve of plasma levels of orally administered domperidone in the rat is greater for deuterated domperidone compounds 2 and 6 compared to non-deuterated domperidone. The table below shows the reduced formation of metabolites in human hepatocytes for domperidone compounds 2 and 6 over a 60 min time period compared to non-deuterated domperidone.

Percentage of metabolite formation in human hepatocytes

Sample % oxidative metabolite % sulfonated metabolite Domperidone 0 min 0.08 0 Domperidone 30 min 2.64 0.23 Domperidone 60 min 3.79 0.37 Connection 2 0 min 0 0 Connection 2 30 min 0.15 0.01 Connection 2 60 min 0.21 0.02 Connection 6 0 min 0.03 0 Connection 6 30 min 1.42 0.13 Connection 6 60 min 1.91 0.22

Another way to reduce the metabolism of domperidone involves administering the drug sublingually so that the active substance goes directly into the bloodstream and bypasses the digestive system where metabolism occurs. A sublingual form of domperidone or deuterated domperidone, formulated as a tablet, film, or other suitable dosage form, can be administered at a lower dose but with efficacy comparable to that of the orally administered form. The pharmacokinetics of domperidone, in particular its t _1/2 , pKa, log P and Kd, make it favorable for sublingual administration.

Another way to reduce the metabolism of domperidone is to administer the active substance in a particulate form that provides a larger surface area. For example, domperidone or deuterated domperidone may be formulated as microparticles or nanoparticles. Using the Biopharmaceutical Classification System (BCS), it is known that Class II drugs

- 12 045546 have high permeability and low solubility, thus their bioavailability is limited by the rate of their dissolution. In this embodiment, the microparticle or nanoparticle or other dosage form that provides increased surface area increases bioavailability by increasing the dissolution rate and can be administered at a lower dose, but with efficacy comparable to that of the orally administered form.

It should be understood that other dosage forms can achieve similar or identical results, for example, the use of spray, powder, thin film, etc. compositions, and using either domperidone or deuterated domperidone.

It should be understood that the embodiments may be used in combination. As one example, a microparticulate or nanoparticulate form of domperidone may be applied or incorporated into a thin film and administered sublingually. As another example, the deuterated form of domperidone can be formulated as microparticles or nanoparticles and can, in some embodiments, be administered sublingually, such as in or on a thin film, spray, etc. In these example combinations, the dose of domperidone can be further reduced due to its increased bioavailability and decreased metabolism.

The following drugs and dosage forms can be used for both deuterated and non-deuterated forms of domperidone.

Nanoparticles can be prepared using dry grinding or wet grinding. Examples of dry grinding methods include those disclosed in US Patent Publications No. 2013/0209569, 2010/0092563, 2014/0287039, 2014/0200276, 2014/0194487, 2014/0255494, 2013/0243854, 20 14/0248359, 2014/0256781, 2014 /0302127, 2014/019395, 2014/0220121, 2012/0135048, 2014/0326812, 2009/0028948 and US Patent No. 9089471; 9095496; 9180096; 9173854; 9017721; 8679544; 8999387; 8734847; 8992982; 9180096; 9186328; 8735450; and 8808751. An exemplary wet grinding method is disclosed in US Pat. No. 9107827. Any of these dosage forms, including but not limited to thin films, tablets, sprays, solutions, etc., includes a sublingual dosage form.

Domperidone, both deuterated and non-deuterated forms, can be administered through the skin, i.e. transdermal. Skin absorption, also called transdermal delivery, transdermal delivery, or dermal delivery, transports domperidone from the outer surface of the epidermis into both the skin and the systemic circulation. The epidermal surface is the primary route of absorption for transdermal delivery, although small amounts may also be transported through hair follicles or glands. Starting at the surface of the epidermis, the product passes through seven epidermal layers before it enters the dermis, from which the product enters the circulatory and/or lymphatic system. The stratum corneum of the epidermis is the outer or superficial layer of the skin and is the rate-limiting barrier to the penetration of external agents, thus the rate of passage through the stratum corneum determines the overall absorption. The main components of the stratum corneum are lipophilic compounds, cholesterol, cholesterol esters and ceramides. Agents with greater lipid solubility therefore penetrate the stratum corneum more quickly and reach the systemic circulation than agents with less lipid solubility, but most all agents penetrate the stratum corneum to some extent. The solubility of domperidone is related to its pH; Domperidone is a weak base, pK _a 7.89, with limited solubility in water with a lipid to water ratio of 3.90.

The health and integrity of the stratum corneum affects the penetration of substances. For example, substances such as strong acids that damage or destroy the composition of the stratum corneum are quickly absorbed. Damage to the skin due to burns, abrasions, wounds and disease also affects absorption. Some solvents, such as dimethyl sulfoxide (DMSO), increase the permeability of the stratum corneum by acting as carriers and are thus used as penetration enhancers or promoters. Some surfactants, such as sodium lauryl sulfate, increase the penetration of water-soluble substances through the skin, possibly by increasing the penetration of water through the skin.

Transdermal delivery can be achieved by topical administration, environmental exposure and/or injection. Skin absorption depends on substance factors including, but not limited to, concentration, molecular weight and lipophilic/hydrophilic nature or solubility, as well as duration of contact, physical condition of the skin, surface of application, and the presence or absence of hair follicles at the surface of application. . For example, absorption of a substance from various surfaces of the skin occurs according to the following pattern from fastest to slowest: scrotum > forehead > axilla > skull > back > abdominal cavity > lower surface of the palm/foot, thanks to the keratinized multilayered squamous layer of the stratum corneum, the function of which is preventing water loss from underlying tissues.

Cutaneous application of domperidone may allow more localized therapy and may avoid or minimize first-pass hepatic metabolism. Thus, dermal administration can achieve higher systemic concentrations. Dosage forms for dermal administration include patches, lotions, liniments, ointments, tinctures, creams, powders, aerosols, gels, etc. The patches may be controlled release and may provide domperidone release over 7 days, in one embodiment. Patches may include a penetration enhancer, which may facilitate delivery or in some cases be essential for delivery.

In the transdermal patch, domperidone or a prodrug of domperidone is present as the free base and/or salt.

The amount of domperidone that is absorbed following transdermal administration can be measured directly or indirectly using methods known in the art and as described below. Even with in vivo studies, species differences may be noticeable. In addition, various previously described compositions may affect the concentrations delivered. Direct measurement of concentration can be achieved using in vivo methods by directly applying domperidone to the skin and measuring domperidone in the blood and urine at a set time, then plotting the results and measuring the area under the curve (AUC). Ex vivo methods can be used because the permeability of the stratum corneum does not change significantly when the skin is carefully removed. Chamber studies using any dosage form of domperidone (e.g. films, patches, lotions, etc., see e.g. Basu, IRJP, 3 (2012), 134-45; Madishetti et al. Daru, 18 (2010) , 221-29; Khan et al. Bull. Pharm. Res. 2 (2012), 15-21) applied to one surface of an isolated skin sample, and measuring its concentration on another surface of the same sample, it is known, for example, using an isolated perfused porcine flap (Riviere, Fundam). Appl. Toxicol. 7 (1986), 444-53). In vitro methods include static and flow diffusion cells, examples of which are Franz cells and Bronaugh cells (Bronaugh and Stewart, J. Pharm. Sci, 74 (1985), 64-67), respectively. The static Franz cell device has an upper donor chamber and a lower receiving chamber containing liquid, with the upper and lower chambers separated by a skin sample as a membrane. The receiving fluid in the lower chamber is typically a buffered saline solution with a known amount of protein, such as bovine serum albumin or body fluid, and is in contact with the skin membrane. In use, a known volume and concentration of domperidone in the vehicle is applied to the upper chamber and penetrates the skin membrane to diffuse or otherwise enter the receiving fluid in the lower chamber. This receiving fluid is sampled, typically through a sampling port through which the extracted fluid volume is also replaced, and analyzed at regular intervals to determine the amount of domperidone that has penetrated the skin membrane. The Brono flow cell is similar to the Franz flow cell, but uses a flow system in a lower chamber from which samples are collected and analyzed continuously rather than at specified points in time.

Methods for transmucosal delivery of domperidone are disclosed in US Publication No. 2010/0255096. Mucoadhesive delivery technologies provide safe and effective delivery of a drug such as domperidone. These mucoadhesive delivery technologies include all diffusion methods in the oral mucosa: passive diffusion, including transcellular (through cells) and paracellular (through lipid-rich domains around cells), carrier-mediated transport, and endocytosis/exocytosis for active cellular uptake and endocytic excretion.

Mucous membranes line the body cavities, which are either exposed to external environmental influences or are internal organs. The oral mucosa is the mucous membrane lining the inside of the mouth and is composed of stratified squamous epithelium (oral epithelium) and underlying connective tissue (lamina propria). It can be further divided into three main categories based on function and histology: the masticatory mucosa of keratinized stratified squamous epithelium, present on the dorsum of the tongue, hard palate and attached gingiva; lining mucosa of non-keratinized squamous epithelium, present almost everywhere in the oral cavity, including the buccal mucosa, which lines the cheeks, the labial mucosa, which is the inner mucosa of the lips, and the alveolar mucosa, which is the mucosa between the gums and the buccal/lip mucosa; and specialized mucosa in the regions of the taste buds on the lingual papillae on the dorsal surface of the tongue. Bioadhesive polymers adhere to any wet surface, such that the mucoadhesive/bioadhesive composition adheres to saliva-moistened keratinized and non-keratinized mucosa.

Examples of transdermal compositions are presented below, all percentages are w/w. Although the following compositions refer to domperidone, one skilled in the art will appreciate that domperidone can refer to either domperidone or deuterated domperidone.

- 14 045546

Compositions Composition 1 Domperidone 1% Dimethyl sulfoxide as needed up to 100% 2 Domperidone 1% Diethyl sebacate 15% Dimethyl sulfoxide as needed up to 100% 3 Domperidone 1% Diisopropyl adipate 20% Dimethyl sulfoxide as needed up to 100% 4 Domperidone 1% Dimethyl isosorbide 15% Dimethyl sulfoxide as needed up to 100% 5 Domperidone 1% Dipropylene glycol 10% Dimethyl sulfoxide as needed up to 100% 6 Domperidone 1% Hexylene glycol 12% Dimethyl sulfoxide as needed up to 100% 7 Domperidone 1% Propylene carbonate 5% Dimethyl sulfoxide as needed up to 100% 8 Domperidone 1% TRANSCUTOL® 20% Dimethyl sulfoxide as needed up to 100% 9 Domperidone 1% Lauric acid diethanolamide 15% Dimethyl sulfoxide as needed up to 100% 10 Domperidone 1% PEG 400 20% Dimethyl sulfoxide as needed up to 100% P Domperidone 1% Cocamide DEA 5% Dimethyl sulfoxide as needed up to 100% 12 Domperidone 1% Oleic acid 20% Dimethyl sulfoxide as needed up to 100% 13 Domperidone 1% PEG-7 methyl ether 20% Dimethyl sulfoxide as needed up to 100% 14 Domperidone 1% Polysorbate 80 15% Dimethyl sulfoxide as needed up to 100% 15 Domperidone 1% BRIJ® L23 69 LQ 5% Dimethyl sulfoxide as needed up to 100% 16 Domperidone 1% BRIJ® S 20 So MH 5% Dimethyl sulfoxide as needed up to 100% 17 Domperidone 1% BRIJ® L4 LQ 5% Dimethyl sulfoxide as needed up to 100% 18 Domperidone 1% Isopropyl palmitate 8% Dimethyl sulfoxide as needed up to 100% 19 Domperidone 1% Levulinic acid 5% Dimethyl sulfoxide as needed up to 100% 20 Domperidone 1% Lauryllactate 5% Dimethyl sulfoxide as needed up to 100% 21 Domperidone maleate 1% Dimethyl sulfoxide as needed up to 100% 22 Domperidone maleate 1% Diethyl sebacate 15% Dimethyl sulfoxide as needed up to 100%

- 15 045546

2e Domperidone maleate 1% Diisopropyl adipate 20% Dimethyl sulfoxide as needed up to 100% 24 Domperidone maleate 1% Dimethyl isosorbide 15% Dimethyl sulfoxide as needed up to 100% 25 Domperidone maleate 1% Dipropylene glycol 10% Dimethyl sulfoxide as needed up to 100% 26 Domperidone maleate 1% Hexylene glycol 12% Dimethyl sulfoxide as needed up to 100% 27 Domperidone maleate 1% Propylene carbonate 5% Dimethyl sulfoxide as needed up to 100% 28 Domperidone maleate 1% TRANSCUTOL® 20% Dimethyl sulfoxide as needed up to 100% 29 Domperidone maleate 1% Lauric acid diethanolamide 15% Dimethyl sulfoxide as needed up to 100% thirty Domperidone maleate 1% PEG 400 20% Dimethyl sulfoxide as needed up to 100% 31 Domperidone maleate 1% Cocamide DEA 5% Dimethyl sulfoxide as needed up to 100% 32 Domperidone maleate 1% Oleic acid 20% Dimethyl sulfoxide as needed up to 100% 33 Domperidone maleate 1% PEG-7 methyl ether 20% Dimethyl sulfoxide as needed up to 100% 34 Domperidone maleate 1% Polysorbate 80 15% Dimethyl sulfoxide as needed up to 100% 35 Domperidone maleate 1% BRIJ® L23 69 LQ 5% Dimethyl sulfoxide as needed up to 100% 36 Domperidone maleate 1% BRIJ® S 20 So ΜΗ 5% Dimethyl sulfoxide as needed up to 100% 37 Domperidone maleate 1% BRIJ® L4 LQ 5% Dimethyl sulfoxide as needed up to 100% 38 Domperidone maleate 1% Isopropyl palmitate 8% Dimethyl sulfoxide as needed up to 100% 39 Domperidone maleate 1% Levulinic acid 5% 40 Domperidone maleate 1% Lauryllactate 5% Dimethyl sulfoxide as needed up to 100% Dimethyl sulfoxide as needed up to 100% 41 Domperidone maleate 1% DURO-TAK® 387-2516 79% Dimethyl sulfoxide as needed up to 100% 42 Domperidone maleate 1% DURO-TAK® 387-2516 60% TRANSCUTOL® 20 Dimethyl sulfoxide as needed up to 100%

- 16 045546

43 Domperidone maleate 1% DURO-TAK® 387-2516 68% Hexyl englycol 12% Dimethyl sulfoxide as needed up to 100% 44 Domperidone maleate 1% DURO-TAK® 387-2516 75% BRIJ® S 20 So ΜΗ 5% Dimethyl sulfoxide as needed up to 100% 45 Domperidone maleate 1% DURO-TAK® 387-2516 75% BRU® L4 LQ1 5% Dimethyl sulfoxide as needed up to 100% 46 Domperidone maleate 1% DURO-TAK® 387-2516 60% Diethyl sebacate 20% Dimethyl sulfoxide as needed up to 100% 47 Domperidone maleate 1% DURO-TAK® 387-2516 60% Diisopropyl adipate 20% Dimethyl sulfoxide as needed up to 100% 48 Domperidone maleate 1% DURO-TAK® 387-2516 70% Levulinic acid 10% Dimethyl sulfoxide as needed up to 100% 49 Domperidone maleate 1% DURO-TAK® 387-2516 70% Lauryllactate 10% Dimethyl sulfoxide as needed up to 100% 50 Domperidone maleate 1% DURO-TAK® 387-2516 60% Polysorbate 80 20% Dimethyl sulfoxide as needed up to 100% 51 Domperidone maleate 1% DURO-TAK® 387-2516 55% BRIJ® S 20 So MH 5% TRANSCUTOL® 20% Dimethyl sulfoxide as needed up to 100% 52 Domperidone maleate 1% DURO-TAK® 387-2516 63% BRIJ® S 20 So ΜΗ 5% Hexylene glycol 12% Dimethyl sulfoxide as needed up to 100% 53 Domperidone maleate 1% DURO-TAK® 387-2516 70% BRIJ® S 20 So MH 5% BRIJ® L4 LQ 5% Dimethyl sulfoxide as needed up to 100% 54 Domperidone maleate 1% DURO-TAK® 387-2516 55% BRIJ® S 20 So ΜΗ 5% Diisopropyl adipate 20% Dimethyl sulf oxide as needed up to 100% 55 Domperidone maleate 1% DURO-TAK® 387-2516 65% BRIJ® S 20 So ΜΗ 5% Lauryllactate 10% Dimethyl sulfoxide as needed up to 100% 56 Domperidone maleate 1% DURO-TAK® 387-2516 54% TRANSCUTOL® 20% BRIJ® L4 LQ 5% Dimethyl sulfoxide as needed up to 100%

- 17 045546

57 Domperidone maleate 1% DURO-TAK® 387-2516 62% Hexyl englycol 12% BRU® L4 LQ 5% Dimethyl sulfoxide as needed up to 100% 58 Domperidone maleate 1% DURO-TAK® 387-2516 54% Diethyl sebacate 20% BRU® L4 LQ 5% Dimethyl sulfoxide as needed up to 100% 59 Domperidone maleate 1% DURO-TAK® 387-2516 54% Diisopropyl adipate 20% BRU® L4 LQ 5% Dimethyl sulfoxide as needed up to 100% 60 Domperidone maleate 1% DURO-TAK® 387-2516 64% Lauryllactate 10% BRU® L4 LQ 5% Dimethyl sulfoxide as needed up to 100% 61 Domperidone maleate 1% DURO-TAK® 387-2516 54% TRANSCUTOL® 10% BRU® L4 LQ 5% Diethyl sebacate 10% Dimethyl sulfoxide as needed up to 100% 62 Domperidone maleate 1% TRANSCUTOL® 40% BRU® L4 LQ 5% Diethyl sebacate 20% Dimethyl sulfoxide as needed up to 100% 63 Domperidone maleate 5% TRANSCUTOL® 40% BRU® L4 LQ 5% Diethyl sebacate 20% Dimethyl sulfoxide as needed up to 100% 64 Domperidone maleate 10% TRANSCUTOL® 35% BRU® L4 LQ 5% Diethyl sebacate 20% Dimethyl sulfoxide as needed up to 100% 65 Domperidone maleate 1% DURO-TAK® 387-2516 59% TRANSCUTOL® 5% BRU® L4 LQ 5% Diethyl sebacate 5% Limonene 5% Dimethyl sulfoxide as needed up to 100% 66 Domperidone maleate 1% DURO-TAK® 387-2516 74% Limonene 5% Dimethyl sulfoxide as needed up to 100% 67 Domperidone maleate 1% DURO-TAK® 387-2516 64% TRANSCUTOL® 5% BRU® L4 LQ 5% Diethyl sebacate 5% Dimethyl sulfoxide as needed up to 100% 68 Domperidone 1% DURO-TAK® 387-2516 64% TRANSCUTOL® 5% BRIJ®L4 LQ 5% Diethyl sebacate 5% Dimethyl sulfoxide as needed up to 100% 69 Domperidone maleate 1% DURO-TAK® 387-2516 59% TRANSCUTOL® 5% BRU® L4 LQ 5% Diethyl sebacate 5% Limonene 5% Dimethyl sulfoxide as needed up to 100

One embodiment is a composition and method for treating gastroparesis using domperidone or deuterated domperidone or a pharmaceutically acceptable salt thereof provided in a sublingual dosage form. Examples of sublingual dosage forms include sublingual tablets, biocompatible thin films, and sublingual sprays. For example, sublingual tablets can be prepared as rapidly disintegrating tablets (RDTs). RDTs are solid dosage forms containing a drug that disintegrate rapidly (<30 s) when placed on or under the tongue, i.e. upon contact with saliva. Formulation of domperidone or deuterated domperidone as an RDT allows domperidone to be administered orally without water or without chewing. Commercially available RDT technologies

- 18 045546 includes lyophilized tablets, compressed tablets, molded tablets, spray-dried powders, thin films and cotton candy systems (McLaughlin et al., Pharmaceutical

Technology, Supplement to September 2009 issue).

One embodiment is a composition and method for treating gastroparesis using domperidone or deuterated domperidone or a pharmaceutically acceptable salt thereof in the form of biocompatible nanoparticles. In one embodiment, domperidone or deuterated domperidone is formulated as a topical composition. In one embodiment, domperidone or deuterated domperidone is formulated as included in and/or applied to the film, either directly or indirectly. For example, domperidone or deuterated domperidone may be formulated to be contained in a film matrix, or may be formulated as a film layer, or may be formulated in a vehicle that is applied to the film. The carrier may be a suspension, foam, emulsion, etc. In one embodiment, domperidone or deuterated domperidone is formulated as a topically applied foam. In one embodiment, domperidone or deuterated domperidone is formulated to be contained in or on a nanoparticle or in association with a nanoparticle. In other embodiments, domperidone or deuterated domperidone is formulated as a solid tablet or in a liquid such as a syrup, suspension, solution or emulsion, or as an injectable preparation.

Thin film compositions include, but are not limited to, those disclosed in US Patent Publications No. 2014/0271788, 2014/0272220, 2014/0271787, 2014/0163060, 2014/0070440, 2014/0017299, 2013/033383 1 and 2013/0220526.

Nanoparticle compositions include any nanoscale structure, which includes, but is not limited to, quantum dots, including graphene quantum dots, graphene-oxide quantum dots and zinc oxide-graphene quantum dots, nanotubes, including graphene nanotubes and/or carbon nanotubes, fullerenes, buckyballs , dendrimers, liposomes, aptamers, micelles, etc.

The compositions easily provide patient compliance and optimal dosage for the treatment of symptoms of gastroparesis. It should be understood that other gastric motility disorders can also be treated using the disclosed compositions and methods.

In one embodiment, a solution or suspension of domperidone or deuterated domperidone is placed in a blister pack and lyophilized to form a unit dose. The lyophilized suspension may include conventional particles, micronized particles or nanoparticles. The following lyophilized technology platforms include ZYD1S® (Catalent), LYOC™ (Cephalon), PHARMAFREEZE® (SPI Pharmaceuticals) and QUICKSOLV® (Janssen).

For a lyophilized RDT product for sublingual administration, domperidone or deuterated domperidone as an active pharmaceutical ingredient (API) is dispersed in a matrix of a polymeric excipient, such as gelatin, and a saccharide, typically mannitol, dissolved in water. In the finished product, the glassy amorphous structure of the polymer component imparts strength and elasticity while maintaining some flexibility. The specific grade of gelatin and its associated dissolution characteristics ensure smooth and rapid melting in the mouth. Mannitol crystallizes during the freezing process, providing an attractive appearance and rigidity, as well as providing stability to the product during processing and transportation. Mannitol is highly soluble and therefore improves texture, taste and mouthfeel. Domperidone or deuterated domperidone can be dissolved in a matrix or dispersed to form a homogeneous suspension for dosing. Liquid dosing provides good dose uniformity and is suitable for very low doses, such as microgram doses. The suspension may be suitable for doses up to 400 mg, and the domperidone or deuterated domperidone is usually micronized. Particle size matters because particles >50 µm may feel lumpy. Products in solution form, due to the freezing point lowering of the soluble API, can be used in doses up to 60 mg. Both solution and suspension products use finely divided domperidone or deuterated domperidone in a dried block form to promote rapid dispersion and a smooth taste. Other excipients described below may be included. Domperidone or deuterated domperidone is dispensed into preformed blister packs and quickly cooled with liquid nitrogen for rapid freezing.

Freezing results in the formation of a network of ice crystals, which sublimate during lyophilization to form a highly porous structure. The matrix components retain the structure of the dried block, but upon contact with moisture, high porosity leads to rapid penetration of water. The matrix dissolves quickly, resulting in rapid disintegration (<10 s).

Once frozen, domperidone or deuterated domperidone is lyophilized, dispensed and dried in blister packs, which are sealed for physical and environmental protection. The product adheres slightly to the packaging, resulting in minimal movement of the product in the blister pockets for stability during transport. The product is

- 19 045546 lamellar structure, but with minimal fragility and sufficient strength that it can be removed from the packaging without destruction.

The lamellar structure and high porosity of lyophilized RDT compositions indicate that water is usually the main component of the dispensed composition, so the weight of the dried product is significantly reduced and is often determined, as a rule, by the dose of domperidone or deuterated domperidone. The recommended 500 mg weight limit for RDT is likely to approach the highest dose of domperidone or deuterated domperidone in lyophilized formulations, which is offset by its rapid breakdown.

Once administered and rapidly dispersed onto or under the tongue, the lyophilized composition is effectively converted into a stock solution or suspension of domperidone or deuterated domperidone. In summary, the lyophilized RDT tablet provides the convenience of a solid oral dosage form with the benefits of a solution/suspension product, suitability for buccal and sublingual administration to enhance bioavailability directly into the systemic circulation and avoidance of pre-systemic metabolism to minimize unwanted metabolites, as well as physical and chemical stability with a shelf life comparable to conventional tablets, i.e. 2-5 years.

QUICKSOLV® begins with an aqueous dispersion of domperidone or deuterated domperidone and a matrix component, which is formed and frozen. Water is removed from the frozen matrix by lyophilization or immersion in alcohol (solvent extraction) to produce a dry block. The resulting product has uniform porosity and sufficient strength to be handled with properties similar to those previously described.

LYOC™ starts as an oil-in-water emulsion and is placed directly into blister cavities followed by freeze-drying. To maintain homogeneity during the freezing process, polymers must be included to increase the viscosity of the matrix to an almost paste-like consistency to prevent sedimentation. Increased matrix viscosity reduces product porosity, which increases freeze-drying time and negatively affects disintegration.

In one embodiment, the relatively low immediate release is an initial dose followed by administration of a sustained release composition. In one embodiment, 10 mg is a low dose immediate release followed by an extended release of 20-30 mg over 24 hours.

Unless otherwise stated, the composition is a dosage form. A tablet is a non-limiting example of a dosage form. Dispersion and disintegration of a dosage form are used interchangeably. In the context of the present invention, the active substance or active substance includes domperidone, domperidone derivatives, domperidone analogues, deuterated domperidone, etc.

The active substance includes all forms of active domperidone, including deuterated forms of domperidone, and also includes, but is not limited to, intermediates, metabolites, enantiomers, polymorphs, crystal structure, hydrates, stereoisomers, salts, bases, complexes, carriers, analogs, derivatives and conjugates. As used herein, extended release and sustained release are generally used interchangeably.

Each of the spherical particles and granules represents any individual component of the dosage form, for example, the capsule shell may be filled with a plurality of spherical particles and/or a plurality of granules.

Modified release (MR) dosage forms include, but are not limited to, the following:

An immediate release composition and a delayed release composition indicate the onset of release of the active substance relative to its administration. Immediate release composition refers to the release of the active substance from the composition beginning within a relatively shorter period of time after administration, for example within a few minutes or less. Delayed release composition indicates that the release of the active substance from the composition does not begin within a relatively shorter period of time after administration, but rather is delayed and begins or is triggered after a relatively longer period of time has passed after administration, for example, more than one hour.

The fast release composition and the slow release composition indicate the rate of release once initiated. Once delivery of the active agent begins, the active agent may be released relatively quickly or relatively slowly. Rapid release indicates that once initiated, the maximum or peak dose is achieved in a relatively shorter period of time. Slow release indicates that once initiated, the maximum or peak dose is achieved over a relatively longer period of time. Once the maximum dose is reached, it can be tapered at any rate, such as fast, slow or constant.

- 20 045546

Extended release composition and sustained release composition indicate a period of continuous release and mean that delivery of the active substance is continued or sustained for an extended period of time after the start of release, typically more than one hour, regardless of the form of the dose release profile. For example, the release of the active substance is maintained between a maximum and a minimum value greater than zero for some relatively longer period of time. This release may be at a constant dose or at a dose that decreases over time.

A sustained release composition indicates the dose that is released. Sustained release means that the active substance is delivered at a relatively constant dose over a medium to extended period of time. This may be represented by a dose release profile that is relatively flat or only slightly sloping once release begins, i.e. without clearly defined peaks and valleys. Thus, sustained release is typically sustained or continuous, but sustained or continuous release may not be sustained.

A pulsatile release formulation indicates that the active substance is delivered in one or more doses that oscillate between a maximum dose and a minimum dose over a specified period of time. This may be represented by a dose release profile having one or more distinct peaks or troughs. However, two or more pulsatile releases can create an overlapping, common, or combined release profile that appears to be constant or is actually constant. When two or more pulsatile releases occur, there may or may not be a period of no release between the pulses. Typically, pulsatile release results in the release of substantially all of the active agent in about 60 minutes or less.

A sustained release formulation provides either release of the active substance within a target dose range over a relatively longer period or plasma drug levels within a target dose range over a relatively longer period, regardless of the specific mechanism or nature of release, e.g. steady, pulsating or continuous.

The release profile for an orally administered drug indicates the manner and time at which the composition releases or delivers the active substance to the stomach, intestines, etc. after introduction. Various methods are known for assessing drug release and obtaining release profiles, including in vitro tests that simulate the in vivo behavior of the composition and which include the USP dissolution test for immediate-release and controlled-release solid dosage forms.

Drug release profiles differ from plasma profiles. The plasma profile indicates the dose or level of active substance in the bloodstream of a mammal, such as a patient, receiving a drug. When the active substance is released from the composition, for example into the intestines, it is possible to determine the amount of active substance present in the bloodstream over time.

The drug release profile can be designed to produce a desired or target plasma profile, and the plasma profile can mimic the release profile. For example, although sustained release of an active substance is expected to produce a steady-state plasma dose and pulsatile release will produce a pulsed (peak and trough) plasma profile, this is not necessarily the case. The half-life (t _1/2 ) of the active substance in the bloodstream (its rate of breakdown) may be such that a steady-state or continuous plasma concentration profile may result from a pulsatile delivery profile. Other factors may also play a role, such as bioabsorption, bioavailability and first pass effect. The plasma profile created by a particular active substance release profile may also vary from patient to patient.

Measurements of bioavailability are known in the art and include the area under the concentration-time curve (AUC) in plasma, maximum concentration ( _Cmax ) and time to reach _Cmax ( _Tmax ).

AUC determines the area under the plasma concentration-time curve and represents the amount of drug absorbed after administration of a single dose of drug (Remington: The Science and Practice of Pharmacy, Editor Gennaro, 2000, p. 999).

Cmax refers to the maximum plasma concentration achieved after oral administration of a drug (Remington, p. 999). Oral administration of a drug results in a single Cmax value but may result in more than one peak plasma concentration, for example, following administration of a pulsatile-dose formulation.

Tmax refers to the period of time required to reach Cmax after oral administration of a drug and is related to the rate of absorption of the active substance (Remington, p. 999).

The term solubility-enhancing polymer or crystallization-inhibiting polymer refers to a water-soluble polymer capable of forming

- 21 045546 a solid dispersion, as defined herein, of weakly alkaline meclizine in a solubility-enhancing polymer, for example, by first dissolving the drug and polymer in the same solvent system and then removing the solvent under appropriate conditions. The weakly alkaline drug is maintained in substantially molecular dispersion or amorphous form during storage, transportation and commercial distribution of a composition containing a solid dispersion of the solubility-enhancing polymer and the weakly alkaline drug.

Controlled release coating includes coatings that delay release, slow release, inhibit release, and/or otherwise prolong the release of drug from controlled release coated particles. The term controlled release covers sustained release, delayed release, and timed pulsatile release, such that a controlled release coating includes a sustained release coating, a timed pulsatile release coating, or a delayed release coating.

The term enteric polymer refers to a pH-sensitive polymer that is stable to gastric acid (ie, relatively insoluble at low pH levels in the stomach) and that dissolves at higher pH levels in the intestinal tract.

Immediate release, with respect to a pharmaceutical composition, which may be a dosage form or a component of a dosage form, refers to a pharmaceutical composition that releases about 50% of the active substance or more, in another embodiment about 75% of the active substance or more, in another embodiment about 90% active substance or more and in other embodiments, about 95% active substance or more within about 1 hour after administration of the dosage form. The term may also refer to pharmaceutical compositions in which a relatively rapid release of the active substance occurs after a delay time during which little or no release of the active substance occurs.

An immediate release (IR) granule or immediate release particle broadly refers to a granule or particle containing an active ingredient that exhibits immediate release properties to the active substance.

The term sustained release (SR) granule or sustained release particle broadly refers to a granule or particle containing an SR coating disposed over an active ingredient containing core.

A delayed release coating or a timed pulsatile release coating (TRP) refers to a controlled release coating combining water insoluble and enteric polymers; The TPR coating itself provides an immediate pulse of active substance release after a predetermined delay time. A timed sustained release (TSR) granule with a TPR coating applied over a barrier coating (SR coating) provides a sustained release profile of the active substance after a specified delay time.

Delayed release (DR) bead or delayed release particle broadly refers to the core containing the active compound. DR coating refers to a controlled release coating containing an enteric polymer, optionally in combination with a plasticizer.

A controlled release (CR) bead or controlled release particle broadly refers to an active compound containing core having an internal SR coating, optionally followed by an external DR or TPR coating, or an internal TPR coating followed by an external DR coating.

Lag time refers to the period of time when less than about 10% of the active substance is released from the pharmaceutical composition after administration of the composition or dosage form containing the composition, or after exposure of the composition or dosage form containing the composition to simulated body fluid(s), e.g. assessed using a USP apparatus using a two-stage dissolution medium (first 2 hours in 700 ml 0.1N HCl at 37°C followed by dissolution testing at pH 6.8 obtained by adding 200 ml pH modifier).

Overlying, for example in relation to a coating on top of a substrate, refers to the relative positioning, for example, of the coating with respect to the substrate, but does not require the coating to be in direct contact with the substrate. For example, a first coating located on top of the substrate may be in direct contact with the substrate, or one or more intermediate materials or coatings may be placed between the first coating and the substrate. For example, an SR coating placed on top of an active substance-containing core may refer to an SR coating applied directly to an active substance-containing core or an acid crystal or an acid-containing core, or may refer to an SR coating applied to a protective seal coating on core containing the active substance.

A seal layer or protective seal coating refers to a protective membrane placed over an active substance-containing core or functional polymer coating that protects the particle from abrasion and abrasion during handling and/or minimizes static electricity during processing.

Orodisintegrating tablet or ODT refers to a tablet that disintegrates quickly in the mouth after administration without chewing. The rate of disintegration may vary, but is faster than the rate of disintegration of traditional solid dosage forms (eg, tablets or capsules) that are intended to be swallowed immediately after administration, or faster than the rate of disintegration of chewable solid dosage forms when tested, such as the USP test method < 701>.

The term substantially disintegrates refers to a level of disintegration of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% disintegration .

Disintegration is different from dissolution; disintegration refers to the breakdown or loss of structural cohesion, such as the particles that make up a tablet, while dissolution refers to the solubilization of a solid in a liquid, such as the solubilization of a drug in solvents or gastric fluids.

A water-insoluble polymer is a polymer that is insoluble or very slightly soluble in an aqueous environment, regardless of pH or over a wide range of pH (eg, from 0 to pH 14). A polymer that swells but does not dissolve in an aqueous environment may be water-insoluble.

A water-soluble polymer is a polymer that is soluble, i.e. a significant amount dissolves in an aqueous environment, regardless of pH.

An enteric polymer is a polymer that is soluble, i.e. a significant amount dissolves in the intestinal environment; those. in aqueous environments under neutral to alkaline conditions, and insoluble under acidic conditions (i.e., low pH).

The term gut-soluble polymer or gastrosoluble polymer refers to a polymer that is soluble under acidic conditions and insoluble under neutral and alkaline conditions.

Unless otherwise specified, the number of different coatings or layers described herein (coating weight) is expressed as the percentage increase in particle or granule weight provided by the dried coating relative to the original particle or granule weight before coating. Thus, 10% of the coating mass refers to the dried coating, which increases the particle mass by 10%.

Bioequivalence is the absence of significantly different rates and extents of absorption, with respect to the availability of the active ingredient, when administered at the same dose under similar conditions. Bioequivalence can be measured using pharmacokinetic parameters such as AUC.

One embodiment is an oral dosage form that contains a modified release (MR) composition. In this embodiment, the unit dosage form contains both an immediate release (IR) dosage form and an extended release (XR) dosage form. In the context of the present invention, an immediate release dosage form releases the active substance immediately after administration. In the context of the present invention, the extended release dosage form includes delayed release, timed release, controlled release or extended release forms. In the context of the present invention, a sustained release dosage form releases the active substance at a predetermined rate over a predetermined time to maintain a constant drug concentration over a specified period of time with minimal side effects. Sustained release dosage forms can be prepared by using a variety of compositions, as described below in illustrative but non-limiting examples, including polymeric conjugates of the active agent and liposomal pharmaceutical compositions comprising the active agent.

The delivery system may include a core, seed or matrix, which may or may not be loaded with an active agent, and one or more coating layers comprising the active agent and/or including a layer having release characteristics that control the onset and release characteristics of the active agent. The core, seed, or template can be manufactured or purchased commercially. As just one example, the core may be sugar or microcrystalline cellulose, and the hydrophilic matrix may be derived from, for example, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), poly(ethylene oxide), polyvinyl alcohol, xanthan gum, carbomer, carrageenan, zooglan etc.

- 23 045546

The coating layers may provide immediate release, sustained pulsatile release, or sustained release. Immediate release of the active substance from the immediate release layer can be achieved, for example, by using a very thin layer or coating through which gastric fluids can quickly penetrate, promoting rapid leaching of the active substance; or by including the active substance in a mixture that includes a supporting binder or other inert substance that readily dissolves and releases the active substance in the gastric fluid; or using a supporting binder or other inert substance that disintegrates rapidly upon contact with the gastric fluid, such substance and the active component being rapidly dispersed in the gastric fluid as fine particles. Such rapidly disintegrating and dispersing substances include, for example, lactose and microcrystalline cellulose. Hydroxypropyl methylcellulose is an example of a suspending agent and binder.

Enteric coatings for the delayed pulsatile release component may be pH dependent or pH independent. Enteric coatings for the sustained release component are pH dependent. The pH-dependent coating is activated to release the drug within a known pH range, which typically corresponds to the local pH of the environment in which delayed release is desired. Examples of pH-sensitive coatings include cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinylacetate phthalate, carboxymethyl ethyl cellulose, copolymerized methacrylic acid/methacrylic acid methyl esters, such as, for example, materials known under the trade name EUDRAGIT® L12.5, L100 or EUDRAGIT ® S12.5, S100, or similar compounds used for the preparation of enteric coatings, aqueous colloidal polymer dispersions or re-dispersions can also be used, for example, EUDRAGIT® L 30D-55, EUDRAGIT® L100-55, EUDRAGIT® S100, EUDRAGIT® drug 4110D (Rohm Pharma); AQUATERIC®, AQUACOAT® CPD 30 (FMC); KOLLICOAT MAE® 30D and. 30DP (BASF); EASTACRYL® 30D (Eastman Chemical).

Examples of commercially available pharmaceutical compositions using an enteric system in the form of a coating or layer to prevent dissolution of the active substance in the stomach include CYMBALTA® (duloxetine HCl, Lilly Indianapolis IN), NEXIUM® (esomeprazole, AstraZeneca LP), ACIPHEX® (rabeprazole sodium, Eisai Inc . and Ortho-Mc-Neil-Janssen Pharmaceuticals, Inc.), ASACOL® HD (me-salamin, Procter & Gamble Pharmaceuticals, Inc.), LIALDA® (mesalamine, Shire US), PENTASA® (me-salamin, Shire US ), ENTECORT® EC (budesonide capsules, AstraZeneca), LAMICTAL® XR (lamotrigine tablets, GlaxoSmithKline), KAPIDEX® (dexlansoprazole, Takeda Pharmaceuticals North America, Inc.), CREON® (pan-creatine capsules, Solvay S.A.), ULTRASE® (pancrelipase capsules, Axcan Pharma US), PROTONIX® (pantoprazole, Pfizer) DEPAKOTE® (divalproex sodium, Abbott Laboratories), PRILOSEC® (omeprazole, AstraZeneca), PREVACID® (lansoprazole, Novartis Consumer Health), ARTHOTEC® (diclofenac sodium, Pfizer); STAVZOR® (valproic acid, Noven Therapeutics), TRILIPIXI 4 (fenofibric acid, delayed-release capsules, Abbott Laboratories) and VIDEX® EU (didanosine, Bristol-Myers Squibb).

An alcohol-resistant pharmaceutical composition uses an alcohol-protective agent to prevent or slow the ethanol-induced release of the active substance from the dosage form, which could result in the release of too high a dose of domperidone or deuterated domperidone into the patient, which could then result in a higher _Cmax , potentially causing QT prolongation. By using an alcohol-resistant composition, dose dumping is prevented, eliminating this safety concern. The alcohol-protective substance may be a single substance, such as a polymer, or a combination of substances, such as a combination of polymers, in the excipient solution. The alcohol barrier agent is applied as a layer or coating, or is present in matrix form in alternative embodiments. Alcohol-protective agents include, but are not limited to, organic-based cellulose acetate phthalate, ammonium methacrylate copolymers, methacrylic ester copolymers, methacrylic acid copolymers, natural and synthetic starches, polyalkylene oxides, and natural and synthetic celluloses, including modified celluloses such as hydroxypropyl methylcellulose ( HPMC), hydroxypropylcellulose (HPC), hydroxymethylcellulose (HMC), methylcellulose (MC), hydroxyethylcellulose (HEC) and carboxymethylcellulose (CMC), waxes such as insect and animal waxes, vegetable waxes, mineral waxes, petroleum waxes and synthetic waxes. In one embodiment, the alcohol barrier agent is Eastman C-A-P® organic cellulose acetate phthalate or Cellacefate, NF (Eastman Chemical Company, Kingsport TN USA). The alcohol-protective substance may be present in the composition in an amount sufficient to impart alcohol resistance at a given ethanol concentration, for example, it may be added in amounts of 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 100, 150, 200, 250, 300, 350, 400, 450 and 500%, calculated by

- 24 045546 mass treatment.

In one embodiment, the active ingredient composition includes a plurality of CR and ID particles, wherein each of the CR particles includes a core coated with a layer of water-insoluble polymer, followed by a coating layer comprising an enteric polymer, optionally in combination with a water-insoluble polymer, wherein the core includes domperidone and a pharmaceutically acceptable polymeric binder, followed by a first coating layer comprising a water-insoluble polymer, optionally in combination with a water-soluble polymer, and an optional second coating of an enteric polymer, optionally in combination with a water-insoluble polymer.

One embodiment contains a plurality of CR and IR particles. The CR particle includes a core coated with a layer of water-insoluble polymer, followed by a coating layer comprising an enteric polymer, optionally in combination with a water-insoluble polymer; wherein the core comprises the active substance and a pharmaceutically acceptable organic acid (eg fumaric acid), separated from each other by at least an SR layer. Each IR particle includes an active substance in combination with suitable excipients. In some embodiments, the composition includes an active agent and at least one organic solubility enhancing acid that is capable of creating an acidic pH microenvironment in the coated bead to solubilize the active agent prior to its release into the hostile pH environment of the intestinal tract where the drug is substantially insoluble .

In one embodiment, the CR particles include an inert core (eg, sugar sphere, cellulose sphere, etc.) sequentially coated with a pharmaceutically acceptable organic acid (eg, succinic acid) and a pharmaceutically acceptable binder (eg, hydroxypropylcellulose); SR layer (eg, comprising a pharmaceutically acceptable water-insoluble polymer such as ethylcellulose, optionally plasticized with a pharmaceutically acceptable plasticizer such as triethyl citrate or polyethylene glycol); a layer of active substance and a pharmaceutically acceptable binder (eg povidone); an optional sealing layer (eg, including a water-soluble polymer such as hydroxypropyl methylcellulose); and an SR layer comprising a water-insoluble polymer such as ethylcellulose (EC-10) and an enteric polymer such as hypromellose phthalate, HP-55, and an optional pharmaceutically acceptable plasticizer such as triethyl citrate (TEC).

The pH-independent coating includes substances that are sensitive to enzymatic activation by azoreductases in intestinal bacteria (i.e., azopolymers) or substances that are susceptible to degradation by polysaccharidases in the colon (natural polysaccharides). Non-limiting examples of azopolymers include copolymers of 2-hydroxyethyl methacrylate (HEMA) and methyl methacrylate (MMA). Non-limiting examples of natural polysaccharides include amylose, chitosan, chrondoitin, dextran and xylan.

An enteric polymer is a polymer having a polystyrene equivalent weight average molecular weight (MW) of about 50,000-150,000 and containing carboxyl groups that remain insoluble at pH below about 4 (stomach pH range) but which ionize and thus cause the polymer to dissolve at pH above about 5.0 (intestinal pH range). The enteric polymer may be a film-forming polymer, such as cellulose acetate phthalate (C-A-P), cellulose acetate trimellitate (C-A-T), hydroxypropyl methylcellulose phthalate (HPMCP), methacrylic acid-ethyl acrylate copolymer, hydroxypropyl methylcellulose acetate succinate (HPMCAS), and polyvinylacetate phthalate. (PVAP). MW NRMSR can be around 80000-110000 or 95000-100000. MW for S-A-P can be around 55000-75000 or 68000-80000.

The delayed release component may include delayed release coatings, sustained release matrices, and sustained release osmotic systems. Retard-release coatings can be made using a water-insoluble polymer, a combination of water-insoluble polymers, or a combination of water-insoluble and water-soluble polymers. Conventional slow-release polymers known to those skilled in the art can be used for the slow-release matrix.

Typical retard release coatings include polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, fatty acids and their esters, alkyl alcohols, waxes, zein (prolamine from corn) and aqueous polymer dispersions such as EUDRAGIT ® RS and RL30D, EUDRAGIT® NE30D, AQUACOAT®, SURELEASE®, KOLLTCOAT® SR30D, and cellulose acetate latex.

The granules or spherical particles can be prepared from any pharmaceutically acceptable materials based on compatibility with the active substance and the physicochemical properties of the granules or spherical particles.

Binders include cellulose derivatives such as methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, etc.

- 25 045546

Disintegrants include corn starch, pregelatinized starch, cross-linked carboxymethylcellulose (AC-DI-SOL®), sodium starch glycolate (EXPLOTAB®), cross-linked polyvinylpyrrolidone (PLASDONE XL®), etc.

Excipients include lactose, calcium carbonate, calcium phosphate, calcium sulfate, microcrystalline cellulose, dextran, starches, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, etc.

Surfactants include sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, bile salts, glyceryl monostearate, PLURONIC® line (BASF), etc.

Solubilizers include citric acid, succinic acid, fumaric acid, malic acid, tartaric acid, maleic acid, glutaric acid, sodium bicarbonate, sodium carbonate, etc.

Stabilizers include antioxidants, buffers, acids, etc.

The following information discloses illustrative, but not limiting, methods of preparation.

The core can be produced by extrusion-spheronization, high shear granulation, solution layering or suspension.

During extrusion-spheronization, the active substance and other additives are granulated by adding a binder solution. The wet mass is passed through an extruder equipped with a sieve of a certain size. The extrudates are spheronized in a marumerizer. The resulting granules are dried and sifted.

In high shear granulation, the active ingredient and other additives are dry mixed, then the mixture is wetted by adding a binder solution in a high shear granulator/mixer. The granules are mixed after wetting by a combination of mixing and grinding actions. The resulting granules or pellets are dried and sifted.

In solution or suspension layering, a drug solution or dispersion, with or without a binder, is sprayed onto precursor grains of a specified particle size in a fluidized bed processor or other suitable device, thereby applying the active agent to the surface of the precursor beads. The pellets loaded with the active substance are dried.

The core particles have a diameter of about 50-1500 µm, preferably 100-800 µm. The core particles can be coated in a fluidized bed apparatus with several alternating coating layers. The core may be coated directly with a layer or layers of active agent, and/or the active agent may be incorporated into the core material. A separating or protective layer can be added on top of the active substance containing layer and/or between the active substance layers. A release or protective layer can be added to the surface of the active-loaded core, which can then be coated with an enteric layer to provide delayed pulsatile or sustained release. Another layer of active agent can also be added to the enteric layer, providing a delayed pulsatile or sustained release, to deliver the initial dose. The protective coating can be applied directly over either the active agent-containing core or the active agent-coated core using conventional coating techniques used in the art, such as in-coater coating or fluidized bed coating, with using solutions of polymers in water or suitable organic solvents or aqueous dispersions of polymers. Suitable agents for the protective layer include cellulose derivatives such as hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, aqueous dispersions of ethylcellulose (AQUACOAT®, SURELEASE®), EUDRAGIT® RL 30D, OPADRY®, cellulose acetate, acetate butyrate cellulose , cellulose acetate propionate, ethylcellulose, fatty acids and their esters, waxes, zein and aqueous polymer dispersions such as EUDRAGIT® RS and RL 30D, EUDRAGIT® NE 30D, AQUACOAT®, SURELEASE®, and/or cellulose acetate latex, separately or in combination with hydrophilic polymers such as hydroxyethylcellulose, hydroxypropylcellulose (KLUCEL®, Hercules Corp.), hydroxypropylmethylcellulose (METHOCEL®, Dow Chemical Corp.), polyvinylpyrrolidone, etc. Coating levels range from about 1 to about 6% w/w, preferably from about 2 to about 4% w/w.

An enteric coating layer providing delayed pulsatile release or sustained release is applied to the core, with or without a seal coating, using conventional coating techniques used in the art, such as in-coater coating or fluidized-bed coating, using solutions of polymers in water or suitable organic solvents or aqueous dispersions of polymers. Suitable coating agents are known in the art, for example, commercially available pH-sensitive polymers, such that the active substance is not released in the acidic environment of the stomach (pH < 4.5), but is released and becomes available when the pH-sensitive layer dissolves at higher pH after a certain time or after

- 26 045546 how the drug passes through the stomach.

Enteric polymers for the delayed pulsatile release component and the sustained release component include, for example, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinylacetate phthalate, carboxymethyl ethyl cellulose, copolymerized methacrylic acid/methacrylic acid methyl esters such as, for example, materials known as EUDRAGIT® L12.5, L100 or EUDRAGIT® S12.5, S100, or similar compounds used to prepare enteric coatings. Aqueous colloidal polymer dispersions or redispersions can also be used, for example EUDRAGIT® L 3OD-55, EUDRAGIT® L100-55, EUDRAGIT® S100, EUDRAGIT® preparation 4110D (Rohm Pharma); AQUATERIC®, AQUACOAT® CPD 30 (FMC); KOLLICOAT MAE® 30D and 30DP (BASF); EASTACRYL® 30D (Eastman Chemical).

Enteric polymers providing delayed pulsatile and sustained release can be modified by mixing with other known coating products that are not pH sensitive, such as neutral methacrylic acid esters with a small proportion of trimethylammonioethyl methacrylate chloride, commercially available as EUDRAGIT® RS and EUDRAGIT® RL; a neutral ester dispersion without any functional groups, commercially available as EUDRAGIT® NE30D; and other pH-independent coating products.

The modifying component of the protective layer used over the enteric coating providing delayed pulsatile and sustained release may include a water barrier layer (semi-permeable polymer) that can be applied sequentially after the enteric coating to reduce the rate of water penetration through the enteric coating layer and, therefore, it may increase the lag time for the release of the active substance. Coating is carried out as described above.

Optionally, a protective or coloring top coat can be applied. OPADRY®, OPADRYII® (COLORCON®) and corresponding colored and clear COLORCON® grades can protect the granules from sticking and impart color to the product. In one embodiment, the amount of protective or color coating is from 1 to 6 wt.%, preferably from about 2 to about 3 wt.%. You can also use talc.

Ingredients may be included in the topcoat formula, for example, to provide relief and provide even faster release. Such components include, for example, plasticizers including acetyl triethyl citrate, triethyl citrate, acetyl tributyl citrate, dibutyl sebacate, triacetin, polyethylene glycols, propylene glycol, etc.; lubricants including talc, colloidal silicon dioxide, magnesium stearate, calcium stearate, titanium dioxide, magnesium silicate, etc.

The composition can be included in hard gelatin capsules, either alone or with additional excipients. The composition can be included in a tablet, for example, by incorporating it into a tablet matrix that rapidly disperses the particles upon ingestion. Filler/binders such as microcrystalline cellulose (AVICEL®), soy polysaccharide (EMCOSOY®), pregelatinized starches (STARCH® 1500, NATIONAL® 1551) and polyethylene glycols (CARBOWAX®) are available in the range of from about 5 to about 75% wt./wt., with a preferred range from about 25 to about 50% wt./wt.

Excipients typically include, but are not limited to, one or more excipients including microcrystalline cellulose, soy polysaccharides, calcium phosphate dihydrate, calcium sulfate, lactose, sucrose, sorbitol, etc.; one or more substances that impart fluidity to powders, including highly dispersed silicon dioxide, silica gel, magnesium stearate, calcium stearate, etc.; one or more lubricants to ensure proper tabletting, including polyethylene glycol, leucine, glyceryl behenate, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, etc., present in the range of from about 0.1 to about 10% wt./ wt., with a preferred range from about 0.3 to about 3.0% wt./wt.

Disintegrants are added to disperse the granules after the tablet is swallowed. Disintegrants include, but are not limited to, crosslinked sodium carboxymethylcellulose (AC-DI-SOL®), sodium starch glycolate (EXPLOTAB®, PRIMOJEL®), crosslinked polyvinylpolypyrrolidone (PLASDONE-XL®), etc., present in the range of about 3 to about 15% w/w, with a preferred range of about 5 to about 10% w/w.

In one embodiment, tablets are prepared from particles that are introduced into a mixer with AVICEL®, disintegrants and lubricant, mixed for a specified time (minutes) until a homogeneous mixture is obtained, then the mixture is placed in the hopper of a tablet press to compress the tablets. The compression force used is sufficient to form the tablet but not to break the granules or coatings.

The tablet may have a three-layer structure, where the immediate release component is mixed

- 27 045546 are sewn dry, and the delayed pulsatile release components and sustained release components are granulated wet. The tablet is then obtained by compression into the form of a single-layer or three-layer tablet. Upon dissolution of the layers, each component is released and acts as formulated as follows: for example, immediate release particles provide immediate release, delayed pulsatile release particles provide delayed pulsatile release, and sustained release particles provide sustained release after a lag time.

One embodiment of the invention is an oral dosage form of domperidone or deuterated domperidone that contains, in one dosage form, both an immediate release form and a sustained release form. One embodiment of the invention is an oral dosage form of domperidone or deuterated domperidone that contains, in one dosage form, both an immediate release form and an extended release form.

A dosage form of domperidone or deuterated domperidone that combines both an immediate release formulation of 10 mg, ranging from 5 to 20 mg, and an extended release formulation of 20 mg, ranging from 10 to 80 mg, provides delivery to the patient continuously for about 12 hours This dosage form provides 12 hours of therapy with one dose to the patient, providing patient convenience and long-term therapy, for example, the patient can benefit from a full night of sleep, a full day of work, a full day of rest, etc. d. no symptoms.

In embodiments, the composition of the invention comprises an immediate release (IR) portion or component or an extended release (XR) portion or component, or combinations thereof. The immediate release portion delivers 100% of the immediate release dose in less than 1 hour, and the extended release portion delivers the extended release dose in 12 hours.

A typical dissolution profile, also called release profile, of domperidone is shown in FIG. 2. The drug release percentage approaches 100% in less than or within 1 hour from the immediate release portion of the delivery system, and from the sustained release portion of the delivery system, about 100% is released in 12 hours or less. Fig. 3 schematically represents the simulated plasma concentration of domperidone, where the plasma drug concentration from the immediate-release portion peaks at approximately twice the concentration of the drug from the extended-release portion, which at the same time reaches a plateau of approximately half that from the immediate release portion.

In one embodiment, the active substance can be administered rectally. Rectal administration of the active substance can be 10-20 mg three times a day. For rectal administration, a suppository form can be used. In one embodiment, the composition is administered rectally, for example, in the form of a suppository.

The composition may take various forms or delivery systems. The following dosage forms may be used and are illustrative only and not limiting. Oral dosage forms include tablet, capsule, sachet, soft gel, liquid, gel, strip, film, powder, granule, gel, pulsatile release, coated core, delayed extended release, layered drug, dosage form extended release, capsule containing tablets, granular caplet, multilayer tablet, etc., including combinations thereof, such as capsule containing tablets, granular caplet, multilayer tablet, etc. with an active substance and at least one pharmaceutically acceptable excipient.

The tablet dosage form is known to those skilled in the art. The tablet may be of any shape or size suitable for oral administration, such as round, elliptical, etc. In one embodiment, the tablet may be either immediate release (IR), extended release (XR), or a combination. The tablet may be a two-layer tablet containing IR and XR layers that are adjacent (FIG. 4); a three-layer tablet containing both IR and XR layers separated by a pharmaceutically acceptable buffer layer (Fig. 5); or an XR tablet containing the active substance in the matrix layer and coated with an IR layer of the active substance (Fig. 6).

The composition may also be provided in other delivery forms, for example, in the form of a capsule containing an IR tablet, a stopper and an XR tablet in an osmotic drug delivery system for controlled delivery of the composition over 12 hours (Fig. 7); in the form of a capsule containing IR granules and XR granules mixed in appropriate proportions (Fig. 8); in the form of a capsule containing IR mini-tablets mixed with XR mini-tablets (Fig. 9); in the form of a capsule containing IR beads and XR beads, which are coated with polymers that provide sustained release (Fig. 10); in the form of a capsule containing XR granules, which are coated with an IR layer (Fig. 11) and

- 28 045546

etc. Other forms of delivery of the active substance may be a compressed tablet containing IR beads and coated XR beads, which are included in the tablet (Fig. 12); a compressed tablet containing an XR tablet included in an IR tablet (FIG. 13); or an XR tablet suspended in an immediate release liquid drug solution in a capsule (FIG. 14).

Another form of delivery is a sachet. The sachet may contain a mixture of IR and XR beads or spherical particles (Fig. 15) or it may contain a mixture of effervescent IR beads and coated XR beads (Fig. 16).

Other immediate, extended or delayed, modified and delayed pulsatile release systems are described in each of the following references: US Publication Nos. 2005/0095295, 2005/0106247 and 2007/0264323 and US Patent Nos. 6126699 and 8211465. As one example, US Publication No. 2005/0106247 describes a drug (cyclobenzaprine hydrochloride) in sustained-release particles, such as spherical particles, pellets, granules, etc., having a sustained-release coating comprising a water-insoluble polymer and/or a water-soluble polymer, and some particles contain in a gelatin capsule. As another example, US Publication No. 2007/0264323 describes drug delivery systems (ADDERALL®), such as spherical particles within capsules, tablets or sachets, including coating layers, delayed pulsatile release components, immediate release compositions, intermediate release compositions release, extended release formulations and controlled release capsules. US Pat. No. 6,126,969 describes drug (acetaminophen) delivery systems, such as a combination of coated and uncoated drug particles, for immediate release/sustained release dosage form. US Pat. No. 8,211,465 describes dosage forms for initial release of a drug (NSAID, such as ibuprofen) and subsequent sustained release of the same drug. The osmotic delivery system is described in Patra et al. Osmotic Drug Delivery Systems: Basis and Design Approaches, Recent Patents on Drug Delivery and Formulations, 7 (2013), 1-12.

The active core of the dosage form may be an inert particle or an acid or alkaline buffer crystal, which is coated with a drug-containing film-forming composition. In one embodiment, the water-soluble film-forming composition forms a water-soluble/dispersible particle. Alternatively, the active substance can be obtained by granulation and grinding and/or by extrusion and spheronization of a polymer composition containing the active substance. The amount of active substance in the core depends on the required dose and usually varies from about 5 to 60 wt.%. The polymer coating on the active core typically ranges from about 4 to 20% by weight of the coated particle, depending on the type of release profile desired and/or the coating polymers and solvents selected. Those skilled in the art will be able to select the appropriate amount of active agent to coat or incorporate into the core to obtain the desired dose. In one embodiment, the inactive core may be a sugar sphere or buffer crystal or an encapsulated buffer crystal, such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, etc., which modifies the microenvironment of the active substance to promote its release.

The drug-containing particle can be coated with a sustained release (XR) coating containing a water-insoluble polymer or a combination of a water-insoluble polymer and a water-soluble polymer to form XR granules. In embodiments, the water-insoluble polymer and the water-soluble polymer may be present in a weight ratio of from 100:0 to 65:35, or from about 95:5 to 70:30, or from about 85:15 to 75:25. The sustained release coating is applied in the amount necessary to provide the desired release profile. In embodiments, the sustained release coating is from about 1 to 15% by weight of the coated beads, or from about 7 to 12% by weight of the coated beads.

A modified release dosage form comprising a mixture of two granule populations can be prepared as follows. The drug containing core is prepared by coating an inert particle such as nonpareil grain, acid buffer crystal or alkaline buffer crystal with the active substance and a polymeric binder, or by granulation and grinding, or by extrusion/spheronization to form an IR granule. The IR granule is coated with a plasticized water-insoluble polymer, such as ethylcellulose alone, or in combination with a water-soluble polymer, such as hydroxypropylmethylcellulose, to form an XR granule. Hard gelatin capsules are filled with XR beads alone or in combination with IR beads in the desired ratio to produce modified release (MR) capsules that provide the desired release profile.

IR beads using the following dissolution procedure have been reported to release at least about 70%, in particular at least about 90%, of the active substance within

- 29 045546 min.

USP Apparatus 2 (50 rpm paddles) is used with the following dissolution medium: 900 ml 0.1N HCl (or suitable dissolution medium) at 37°C and the release of the active substance is determined by HPLC.

An aqueous or pharmaceutically acceptable solvent can be used to prepare core particles containing the active substance. The type of film-forming binder used to bind the drug to the inert sugar sphere is not critical, but water-soluble, alcohol-soluble, or acetone/water-soluble binders are typically used. Binders such as polyvinylpyrrolidone (PVP), polyethylene oxide, hydroxypropyl methylcellulose (HPCM), hydroxypropylcellulose (HPC), polysaccharides such as dextran, corn starch can be used in concentrations of about 0.5 to about 5 wt.%, with other concentrations are also used. The active agent may be present in the coating composition in the form of a solution or may be dispersed at a solids content of up to about 35% by weight depending on the viscosity of the coating composition.

The active agent, optionally a binder such as PVP, a dissolution rate controlling polymer if used, and optionally other pharmaceutically acceptable excipients, are mixed in a planetary mixer or high shear granulator such as a FIELDER® and granulated by adding/spraying granulating liquid such as water or alcohol. The wet mass can be extruded and spheronized into spherical particles (pellets) using an extruder/marumerizer. In these embodiments, the active load can be up to 90 wt.% based on the total weight of the extruded/spheronized core.

Illustrative, but non-limiting, examples of water-insoluble polymers used in XR coating include ethylcellulose powder or aqueous dispersion (e.g., AQUACOAT® ECD-30), cellulose acetate, polyvinyl acetate (KOLLICOAT® SR 30D, BASF), neutral copolymers of ethyl acrylate and methyl methacrylate , copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups, such as EUDRAGIT® NE, RS and RS30D, RL or RL30D, etc. Exemplary, but not limiting, water-soluble polymers include low molecular weight hydroxypropyl methylcellulose (HPMC) methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone and/or polyethylene glycol (PEG) with a molecular weight >3000). The sustained release coating is typically applied at a thickness ranging from about 1 to 15% by weight depending on the solubility of the active in water and the solvent or latex slurry coating used.

Coating compositions used to form membranes are typically plasticized. Illustrative, but not limiting, plasticizers include triacetin, tributyl citrate, triethyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, polyethylene glycol, polypropylene glycol, castor oil, dibutyl sebacate and/or acetylated monoglycerides, etc. The plasticizer may be from about 3 to about 30 wt.%, more typically from about 10 to about 25 wt.% based on the weight of the polymer. The type of plasticizer and its content depends on the polymer or polymers and the nature of the coating system (eg, aqueous or solvent based, solution or dispersion based, and total solids content).

The particle surface can be prepared for further processing by applying a thin film of hydroxypropyl methylcellulose (HPMC) (OPADRY® Clear) before applying a sustained release membrane coating to separate the different membrane layers. Typically HPMC is used, but other primers such as hydroxypropylcellulose (HPC) can also be used.

Membrane coatings can be applied to the core using any coating technology used in the pharmaceutical industry. In one embodiment, a fluidized bed coating method is used.

Multi-dose forms can be used, i.e. products in multiparticulate dosage forms (pellets, spherical particles, granules, mini-tablets, etc.) or in other forms suitable for oral administration. In the context of the present invention, these terms are used interchangeably to refer to multiparticulate dosage forms.

A sustained release dosage form that includes a mixture of two or more granule populations can be prepared as follows. An inert particle, such as nonpareil grain, acid buffer crystal or alkaline buffer crystal, is coated with an active substance and a polymer binder to form an active particle, i.e. immediate release (IR) granules, which may be in unit dosage form to act as a bolus dose. The active particle is coated with a solution or suspension of a water-insoluble polymer or a mixture of water-soluble and water-insoluble polymers to form a sustained-release coated active particle, i.e. for extended release (XR). Hard gelatin capsules are filled with XR beads alone and optionally in combination with IR beads in a ratio of 95:5 to 70:30 (ER beads:IR beads) to produce a modified release (MR) capsule exhibiting the target profile. release of the active substance.

In one embodiment, the dosage form has an immediate release portion of the active agent dispersed in an oil or lipid system and another portion that is formulated as a waxy matrix or active agent particles coated with hydrophobic carriers. At least 15-50% of the active substance is an immediate release portion and is in a dosage form suitable for immediate release. The remainder of the tablet-capsule, by weight, may comprise a sustained release composition or a portion of a sustained release composition.

Active domperidone or deuterated domperidone can be formulated as a lipid-based delivery system. Encapsulation or solubilization of the active substance in lipid excipients can lead to increased solubilization and absorption, resulting in increased bioavailability.

Lipid excipients are commercially available. Because lipids influence absorption, it is necessary to know the characteristics of lipid excipients. Factors that determine the selection of excipients for lipid-based compositions include miscibility, solubility, self-dispersibility and ability to promote self-dispersibility of the composition, digestibility and metabolic pathway of digestible products, irritation, toxicity, purity, chemical stability, capsule compatibility, melting point, cost and etc.

Edible oils consisting of medium and long chain triglycerides, along with various solvents and surfactants, are often used to formulate lipid-based compositions. Many lipids are amphiphilic, i.e. have a lipophilic part (fatty acid) and a hydrophilic part. The melting point increases with increasing fatty acid chain length, but the melting point decreases with increasing unsaturation of the fatty acid, which also increases susceptibility to oxidation. Solubilizing agents used in lipid-based compositions are presented in the following table.___________________________

Solubilizing excipients used in oral lipid formulations in commercially available Water-insoluble excipients Triglycerides Surfactants Beeswax Long chain triglycerides Polysorbate 20 (TWEEN® 20) Oleic acid Hydrogenated soybean oil Polysorbate 80 (TWEEN® 80) Soy fatty acids Hydrogenated vegetable oil Sorbitan monolaurate (SPAN® 20) D-a-Tocopherol (vitamin E) Corn oil, Olive oil, D-a-Tocopherol PEG 1000 succinate (TPGS) Corn oil mono-di-triglycerides Soybean oil, Peanut oil G liceryl monooleate

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Medium chain (C8/C10) mono and diglycerides Sesame oil Polyoxyl 3 5 castor oil (CREMOPHOR® EL) Esters propylene glycol and fatty acids Medium chain triglycerides Polyoxyl 40 hydrogenated Castor oil (CREMOPHOR® RH40) Caprylic/capric acid triglycerides isolated from coconut oil or palm oil Polyoxyl 60 hydrogenated Castor oil (CREMOPHOR® RH60) PEG 300 glycerides oleic acid (LABRAFIL® M-1944CS) PEG 300 glycerides linoleic acid (LABRAFIL® M-2125CS) PEG 400 glycerides caprylic/capric acid (LABRASOL®) PEG 1500 glycerides lauric acid (GELUCIRE® 44/14)

Vegetable oil triglycerides are the most commonly used lipid excipients. They are completely digested and absorbed, eliminating safety concerns. Triglycerides are long chain triglycerides (LCT), medium chain triglycerides (MCT) and short chain triglycerides (SCT). Their dissolving power for the active substance is predominantly a result of the effective concentration of the ester groups. MCTs have greater solubility than LCTs and are less prone to oxidation. Oils from different plant sources have different proportions of each fatty acid. The fatty acid composition of various lipid excipients is shown below.

Fatty acid composition found in lipid excipients

Fatty acid chain length (number of atoms carbon) Common name Melting point(°C) 8 caprylic acid 16.5 10 capric acid 31.6 12 lauric acid 44.8 14 myristic acid 54.4 16 palmitic acid 62.9 18 stearic acid 70.1 18 oleic acid 16.0 18 linoleic acid -5.0 18 y-linoleic acid -11.0 18 ricinoleic acid 6.0 20 arachidic acid 76.1 22 behenic acid 80.0

D-a-tocopherol polyethylene glycol 1000 succinate (Vitamin E TPGS) is obtained from plant tocopherols. It is soluble in water and acts as an absorption enhancer for poorly water-soluble drugs. Pure triglycerides are found in refined vegetable oils.

Mixed glycerides are obtained by partial hydrolysis of vegetable oils. The starting materials for the production of triglycerides and the degree of hydrolysis determine the chemical composition of the resulting mixed glycerides. Mixed glycerides with medium chain length are not subject to oxidation, have greater solubility and promote emulsification. These polar oil excipients also improve the solubility and dispersibility of the composition. Examples of polar oils include sorbitan trioleate (SPAN® 85) and oleic acid.

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Co-solvents, such as ethanol, glycerin, propylene glycol, polyethylene glycols (PEG)-400, etc., enhance the solvent's ability to formulate actives and aid in the dispersion of systems that contain a high proportion of water-soluble surfactants. Practical limitations associated with cosolvents include precipitation of the solubilized active from the solvent due to loss of solubility after dilution, the immiscibility of some cosolvents with oils, and the incompatibility of low molecular weight solvents with capsule shells.

Water-insoluble surfactants are lipid excipients with an intermediate hydrophilic-lipophilic balance (HLB 8-12) that adsorb at oil-water interfaces. Depending on the degree of ethoxylation, they have a final solubility in water. They can form emulsions when shear is applied and can be said to be water dispersible. They can form micelles but cannot self-emulsify due to their insufficiently hydrophilic nature. Oleate esters such as polyoxyethylene(20)sorbitan trioleate (TWEEN®-85) and polyoxyethylene(20)glycerol trioleate (TAGOT®-TO) are water-insoluble surfactants with an HLB of 11-11.5. However, a mixture of TWEEN®-80 and SPAN®-80 with an average HLB of 11 is not functionally similar to TWEEN®-85. A mixture of TWEEN®-80 and SPAN®-80 contains both water-soluble and water-insoluble molecules, but TWEEN®-85 contains predominantly water-insoluble molecules.

Water-soluble surfactants are the most widely used surfactants for the formulation of self-emulsifying drug delivery systems. Substances with HDB >12 can form micellar solutions at low concentrations when dissolved in pure water above their critical micellar concentration (CMC). Water-soluble surfactants are synthesized using PEG with hydrolyzed vegetable oils, or alternatively, alcohols can be prepared to react with ethylene oxide to form alkyl ether ethoxylate, a traditionally used surfactant (e.g., CETOMACROGOL™ cetostearyl alcohol ethoxylate). As a result of the reaction of sorbitan esters with ethylene oxide, polysorbates are formed, mainly ether ethoxylates. CREMOPHOR® RH40 and RH60 (ethoxylated hydrogenated castor oil) are examples of this type, obtained by hydrogenation of substances isolated from vegetable oils. CREMOPHOR® EL (ethoxylated castor oil), which is not hydrogenated, is also widely used. CREMOPHOR® enhances absorption by inhibiting efflux pumps; Although the mechanism of inhibition has not been determined, it may be a nonspecific conformational change due to penetration of surfactant molecules into the membrane, adsorption to the surface of efflux pumps, or interaction of molecules with intracellular domains of the efflux pump.

Additives may be used to protect the composition from oxidation. Examples include lipid-soluble antioxidants such as α-tocopherol, β-carotene, propyl gallate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), etc.

The formulation process determines the nature of the lipids, since lipid excipients have different chemical compositions, resulting in wide melting ranges. Thermal properties of lipids, such as crystallization temperature, melting point, glass transition temperature and determination of solid fat content of the excipient as a function of temperature, are assessed using differential scanning calorimetry (DSC). The structure of lipids during heating or cooling is assessed using high temperature microscopy. The crystallinity of the lipid excipient is confirmed by X-ray diffraction (XRD).

High-performance liquid chromatography (HPLC) and gas chromatography (GC) can determine the exact composition of ethers, esters and fatty acid distribution. Other chemical indicators include molecular weight of fatty acids, determined by their saponification value, hydrocarbon chain saturation, determined using an iodine-based assay, oxidative changes, determined by measuring peroxides, free fatty acids, determined by acid content, and free hydroxyl groups, determined by measuring the content of hydroxyl groups.

FDA solubility testing does not correlate with in vivo performance of lipid-based formulations. Lipids in the gastrointestinal tract undergo digestion processes in the presence of lipases (stomach and pancreas), which also affect the emulsification and dispersion properties of lipid excipients, leading to changes in solubilization ability in vivo. Therefore, the digestibility of lipid excipients must be taken into account when selecting lipid-based compositions. Dissolution testing in biorelevant media can evaluate such effects and predict in vivo behavior. The effectiveness of self-emulsifying compositions can be determined by testing dispersions (emulsifying ability and particle size). Photon correlation spectroscopy (PCS) or laser diffraction can be used to measure particle size, and emulsifying ability can be predicted by visual observation.

Lipid-based excipients improve the oral absorption of drugs by influencing various physiological processes, for example, stimulating bile flow and pancreatic juice secretion, prolonging gastric emptying, increasing membrane motility, opening tight cell junctions, promoting lymphatic transport of drugs, thus avoiding pre-systemic metabolism , and inhibiting efflux transporters. Various in vitro models are available to evaluate these effects, including intestinal microsomes, Caco-2 cells, the everted pouch method for intestinal absorption studies using chamber and in situ perfusion assays.

Liposomes can be used; these spherical bilayer structures resemble a cell membrane in their arrangement and are mainly amphiphilic phospholipids (a hydrophilic head part and a hydrophobic tail part, including fatty acids). When hydrated, these phospholipids form spherical bilayer structures oriented such that their hydrophobic tails are oriented toward the interior of the structure and their hydrophilic heads are oriented toward the exterior of the structure. Hydrophilic agents may be incorporated into the inner water spaces of the globules, while hydrophobic active agents may be incorporated into the inner fatty acid layers.

Solid lipid nanoparticles (SLN) can be used. SLNs can improve bioavailability along with controlled and site-specific drug delivery and are therefore potential carriers for intestinal lymphatic delivery of oral drugs. SLNs are typically spherical particles ranging in size from 10 to 1000 nm with a solid lipid core matrix (stabilized by surfactants) that can solubilize lipophilic molecules. Preferably used lipids include monoglycerides such as glycerol monostearate, diglycerides such as glycerol behenate, triglycerides such as tristearin, fatty acids such as stearic acid, steroids such as cholesterol, and waxes such as cetyl palmitate. The oral bioavailability of one drug was improved by formulating an N-carboxymethyl chitosan polymer that coated the drug-loaded SLN using a monoglyceride lipid and the surfactants soy lecithin and poloxamer 188 (Venishetty et al.).

In spray curing, also called spray cooling, molten lipid is sprayed into a cooling chamber and solidifies into spherical solids when exposed to air. Solid particles are collected from the bottom of the chamber and filled into hard gelatin capsules or compressed into tablets. Ultrasonic atomizers generate particulate matter through a spray cooling process. Parameters to be considered are the melting point of the excipient, the viscosity of the composition and the temperature of the cooling air inside the chamber to ensure instantaneous solidification of the droplets. Drug granules have been reported to be prepared by melt granulation using PEG 4000 or poloxamer 188 as a meltable binder and lactose monohydrate as an excipient. Microparticles with a narrow size distribution have been reported when stearoylpolyoxyglycerides (GELUCIRE® 50/13) were used as an excipient and they significantly increased the solubility of poorly water-soluble drugs (Cavallari et al.).

Melt granulation, also called pelletization, converts a powdered mixture of active substance into granules or pellets. Fusible binder (in molten state) is sprayed onto the powder mixture during high shear mixing (pumping method), or fusible binder is mixed with the powder mixture and melted due to friction of particles (solid/semi-solid) during high shear mixing process. The molten binder forms liquid bridges between the powder particles and forms small granules that transform into spheronized particles under controlled conditions. Depending on the particle size of the powder, 15-25% lipid-based binder can be used. Parameters to consider during this process include binder particle size, mixing time, mixer speed, and binder melt viscosity. The drug dissolution rate has been improved by formulating melt agglomerates containing solid drug dispersions (Seo et al.). The lactose monohydrate is melt agglomerated using a fusible binder such as PEG 3000 GELUCIRE® 50/13 in a high shear mixer.

Polyoxylglycerides, partial glycerides or polysorbates and lecithins are examples of lipid excipients used in the melt granulation method to form self-microemulsifying systems.

In embodiments, sustained release matrix tablets can be prepared using hydrophobic carriers or fusible vehicles such as stearic acid, carnauba wax, and beeswax by melt granulation methods, rendering the carriers hydrophobic for long-term delivery.

In one embodiment, a pulsatile release form is used. The pulsatile release form includes an active core having one or more coatings, called a coated core composition. The coated core can also be used in combination with an amount of active substance suitable for immediate release.

In one embodiment, an amount of active substance formulated to be immediately released, in combination with at least a second amount of active substance, formulated such that the second amount begins to be released after a certain delay and that the release of the second portion is or may be sustained over a period of time. time is called a delayed extended release dosage form. Each of these pulsatile release dosage forms is described below in all weight percentages unless otherwise indicated.

The coated core composition is an active core dosage form that includes an inert particle such as a commercially available nonpareil sugar sphere. The amount of active substance in the core varies depending on the desired dose for delivery. In one embodiment, the core contains from about 5 to about 90% active material. In one embodiment, the core contains from about 5 to about 60% active material. The amount of active substance is indicated based on the total weight of the kernel. Those skilled in the art will be able to select the appropriate amount of active material to coat or incorporate into the core to obtain the desired dosage form. Typically, the coated core may include from about 80, 160 and up to about 480 mg of active ingredient. An aqueous or pharmaceutically acceptable solvent medium may be used to coat the core particles. Any type of pharmaceutically acceptable inert binder may be used to bind the active agent to the inert particle. Water-soluble binders can be used. Alcohol-soluble binders can be used. Binders such as polyvinylpyrrolidone (PVP), carboxyalkylcellulose, polyethylene oxide, polysaccharides such as dextran, corn starch, hydroxypropyl methylcellulose (HPMC (former name) or hypromellose (current name)), hydroxypropyl cellulose, etc. can be used by dispersing them in water in a concentration of about 0.5 to 5 wt.%. The active substance may be present in this coating composition in the form of a solution or in the form of a suspension. The concentration of active agent may vary from about 0.1 to about 20 wt.% depending on the viscosity of the coating composition.

In one embodiment, the active core is prepared by granulation or extrusion and spheronization. The active agent, a binder such as PVP, an optional dissolution rate-controlling polymer such as high viscosity HPMC (hypromellose), and optionally other pharmaceutically acceptable excipients are mixed in a high shear granulator (eg, a FIELDER® granulator) or a fluidized granulator. layer (eg GLATT® GPCG granulator), granulate to form agglomerates by adding/spraying a granulating liquid such as water or alcohol and dry.

The wet mass is extruded and spheronized to form spheroidal particles (spherical particles) using an extruder. In these embodiments, the drug loading may be 90 wt.% based on the total weight of the extruded or granular core.

In one embodiment, one layer of the membrane coating on the particle containing the active substance includes a plasticized enteric polymer, and the other layer includes a mixture of a water-insoluble polymer and a plasticized water-dispersible/enteric polymer. The water-insoluble polymer and the water-dispersible polymer are present in a weight ratio of about 10:1 to 1:1 or about 4:1 to 1:1. The total weight of the coatings ranges from about 15 to 80 weight percent, or from about 20 to about 60 weight percent, based on the total weight of the multiparticulate dosage form.

An intermediate acid membrane is optional. If included, the intermediate acid-containing membrane may include an organic acid, such as fumaric acid, citric acid, succinic acid, tartaric acid, malic acid, maleic acid, etc.; and a binder such as PVP. Typically, water-soluble polymers or alcohol-soluble polymers are used. The weight of such an acid-containing membrane ranges from about 5 to about 20% based on the total weight of the coated spherical particles. The acid in the acid-containing membrane delays the dissolution of the enteric polymer in the inner layer, thereby increasing the delay time as well as decreasing the rate of release of the active substance from the coated spherical particle. The composition of the outer layer of the polymer membrane and the individual weight of the inner, intermediate and outer membrane layers are further optimized to achieve pulsatile release profiles for the active substance based on predicted in vitro/in vivo correlations. Thus, a pulsatile release dosage form is optimized to release a specific amount of active substance over a specific period of time and/or at a specific point in the digestive tract of the individual being administered

- 35 045546 drug.

Examples of enteric polymers include, but are not limited to, the following compounds or compositions, alone or in combination: esters of cellulose and its derivatives (cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate), polyvinylacetate phthalate, pH-sensitive methacrylic acid copolymers -methamethacrylate and shellac. These polymers can be used as a dry powder or an aqueous dispersion. Available are EUDRAGIT® L100, S100, L30D methacrylic acid copolymers (Rohm Pharma), CELLACEFATE® cellulose acetate phthalate (Eastman Chemical Co.), AQUATERIC® cellulose acetate phthalate aqueous dispersion (FMC Corp.), and AQOAT® hydroxypropyl methylcellulose acetate succinate aqueous dispersion ( Shin Etsu K.K.).

Examples of water-insoluble polymers include, but are not limited to, the following compounds or compositions, alone or in combination: cellulose derivatives (e.g. ethylcellulose), polyvinyl acetate (KOLLICOAT® SR 30D, BASF), neutral ethyl acrylate-methyl methacrylate copolymers, acrylic ester copolymers and methacrylic acids with quaternary ammonium groups, such as EUDRAGIT® NE, RS or RS30D, RL or RL30D, etc.

Membrane coatings can be applied to the core using any pharmaceutical coating method known in the art. For example, fluidized bed coating can be used.

The pulsatile release dosage form can be prepared by (i) coating an inert particle, such as a nonpareil bean (sugar sphere), with an active substance and a polymer binder or by preparing the particle containing the active substance by granulation and/or extrusion/spheronization to form the active particle; (ii) coating the active particle with a plasticized enteric coating to form a plasticized enteric coated active particle; and (iii) coating the plasticized enteric coated active particle with a mixture of a water-insoluble polymer and an enteric polymer. The release characteristics can be modulated by interchangeability of parts (ii) and (iii). An organic acid, as described above, can be added to the membrane between parts (ii) and (iii) to further modulate the lag time and release profile of the active agent from the particle.

In one embodiment, a single particle form can be used in the composition to provide a time-controlled pulsatile release of the active agent several hours after oral administration or to target specific sites of absorption. In one embodiment, dosage forms comprising active ingredient-containing particles with multiple coating layers are combined into one combination dosage form with a specified amount of immediate release active ingredient, for example, in a gelatin, hard gelatin, or soft gelatin capsule. This embodiment provides a combination dosage form having both an immediate release portion and a time-controlled pulsatile release portion of the active substance.

The optional immediate release portion and the coated core active portion may each include about 10 mg, 20 mg, etc. active substance, and the dosage form comprising the coated core of the present invention may contain from about 10 to 80 mg of active substance.

In one embodiment, a delayed extended release form is used.

In one embodiment, the dosage form may provide at least a bimodal profile of the active substance in the blood, such as the profile shown in FIG. 2. In this embodiment, the dosage form contains at least a first amount of active substance for immediate release and a second amount of active substance for delayed extended release. For example, the first portion of the active substance is immediately released within the first hour after administration from the dosage form of the invention. There is a period of time during which substantially no amount of the active substance is released and/or can enter the bloodstream and/or be bioavailable from the second portion of the administered active substance. Then, after a further period of time, eg several hours, an additional amount of active substance is released, and the release of this second portion occurs over an extended period of time, eg up to 12 hours after the initial administration or even longer. This release of the second portion usually occurs after a delay time during which no active substance is released at all, so dosage forms that can provide a delay before the amount of active substance is released are called delayed extended release dosage forms. Such a dosage form may be administered alone or may be administered in combination with other dosage forms.

It is desirable that the level of the active substance in the blood increases, so that the concentration

- 36 045546 tion in the blood corresponded to the amount of active substance that is bioavailable after immediate release during the first hour after administration. After some time, the level of the active substance in the blood decreases to below the desired or therapeutic level. A second portion of the active substance can enter the bloodstream after the immediate release portion of the active substance has been released. In embodiments, after blood levels of the active agent begin to decrease, the composition desirably increases and/or maintains blood levels at or above approximately the desired concentration without the need to administer a second dose of the active agent.

The following example illustrates one embodiment. The first portion of immediate release of the active substance has an initial pharmacokinetic profile. Fillers, excipients, etc. may provide a finite mass percentage.

Compositions for delayed sustained or extended release are as follows. Each sustained release composition contains a specified amount of active agent and is formulated such that the active agent is released over a period of 4 to 12 hours, typically 6 to 12 hours.

Polyalcohols such as mannitol, coagulants such as POLYOX®, coagulants and lubricants such as stearic acid are added for granulation, which can provide a delayed and sustained release composition. Caplets, tablets or other dosage forms of the delayed release composition are prepared using procedures known in the art, including encapsulation procedures. Such dosage forms, no more, no less, typically exhibit sustained release profiles in the blood, i.e. dosage forms usually release the active substance immediately upon administration and continue to release the active substance over an extended period of time. These compositions may also be formulated into a dosage form and may exhibit sustained release profiles, releasing the active agent over a period of several hours to 12 hours after dosing.

In one embodiment, dosage forms formed from such compositions may optionally be coated with a base to compact tablets for subsequent processing. Sealants include, for example, HPMC, (poly)ethylene glycol (PEG), etc.

In one embodiment, the dosage form is bandaged with one or more strips of one or more polymeric materials, as described below, and is shown in FIG. 17. One or more circumferential or other types of strips of polymeric material are used, for example, relatively insoluble polymeric material, which only minimally or not at all erode or fail during the period of release of the active substance.

Exemplary insoluble polymers include the water-insoluble polymers described above. The number of stripes, the position or distance between stripes, and the thickness of the stripes can control the rate of release of the active substance. For example, there may be an offset of 0.5, 1.0, 1.5, 2.0, 2.5, or 3.0 mm between strips if multiple strips are used. For example, each strip may have a width of 0.5, 1.0, 1.5 or 2.0 mm and have a thickness of from about 0.1 to 100 µm, or from 0.1 to 50 µm, or from 0.1 to 20 microns. As shown in FIG. 17, in one embodiment, the caplet has two circular polymer strips, each strip 20 and 30 having a width of about 1 mm, with a distance 40 between the strips of about 2 mm. The bandaged dosage form slows the release of the active substance and prolongs the period of time during which the active substance can be released and/or enter the bloodstream, i.e. be bioavailable. In embodiments, the strip(s) delay the onset of release of the active agent so as to provide a delay time, also referred to as delayed onset or delayed release, during which no amount of the active agent is released. The delay in onset of release may be 0 to 4 hours, or may be 0 to 3 hours, or may be 0.5 to 4 hours, or may be 1 to 2 hours after administration.

The enteric coating may also include other excipients or fillers, such as talc, lactose, dicalcium phosphate, lubricants such as magnesium stearate, etc.

The bandaged dosage form can be coated, such as an enteric coating, at a level of about 2 to 10 μg/cm ² , typically about 7 μg/cm ² . The enteric coating delays the onset of action of the active substance so that there is a time during which no amount of the active substance is released after administration of the dosage form. Typically, after application of the enteric coating, the delay in the onset of release of the active substance from the coated ligated dosage form (e.g., an enteric-coated ligated caplet) may be 0.5 to 4 hours, typically 1 to 2 hours.

In one embodiment, the immediate release dose of active substance described above is combined with an enteric-coated ligated caplet using methods known in the art to produce a single combination dosage form,

- 37 045546 for example in one gelatin capsule. The composition can be tailored to provide a specific desired blood profile.

In embodiments, the compositions include at least an immediate release composition and a sustained release composition, which will subsequently be described below. Sustained release formulations generally do not demonstrate a delayed onset of action of the active substance. A sustained release composition typically does not exhibit a significant period of time during which no amount of drug becomes bioavailable from the dosage form after administration.

In one embodiment, a capsule tablet is a capsule containing a first portion of the active substance in tablet form that is formulated for immediate release immediately after administration or administration, and at least a second portion of the active substance that is in tablet form that is formulated for sustained release. release, i.e. the second portion continues to release a certain amount of the active substance up to 6-12 hours after administration. At least 15-50% of the active substance is an immediate release composition which is in tablet form and is suitable for immediate release. The remainder of the tablet-capsule, by weight, may comprise a sustained release composition or a portion of a sustained release composition. A tablet containing an immediate release composition and a tablet containing a sustained release composition can be combined in a single dosage form, for example a gelatin capsule, using methods known in the art.

In one embodiment, a granular particle caplet is a capsule or caplet containing a first part of the granular particulate active ingredient that is formulated for immediate release and at least a second part of the active ingredient that is in tablet form that is formulated for sustained release. At least 15-50% of the active substance is an immediate release composition and may be in granules versus a tablet. In one embodiment, at least about 80% of the granule-containing capsule includes an immediate-release active ingredient composition in granular form, typically contained in a single caplet. The remainder of the granular particle caplet, by weight, may comprise a sustained release composition, or the granular caplet may comprise a portion of the sustained release composition. A caplet containing an immediate release composition and a caplet containing a sustained release composition can be combined in a single dosage form, for example a gelatin capsule, using methods known in the art.

In one embodiment, a multilayer tablet comprises a tablet having two or more active agent layers that are formulated for immediate release and an active agent layer formulated for sustained release. The multilayer tablet contains a predetermined amount of active ingredient for immediate release immediately after administration and at least a second portion of active ingredient that can immediately provide a predetermined amount of active ingredient for up to 6-12 hours after administration of the multilayer tablet. At least 15-50% of the active substance is an immediate release composition. In one embodiment, at least about 80% of the multilayer tablet includes an immediate release active ingredient composition. The remainder of the multilayer tablet, by weight, may include a sustained release composition or may include a portion of a sustained release composition. These compositions can be combined in a conventional manner, for example in a tablet press, so that after processing the final tablet dosage form has two or more layers, where at least the first layer contains an immediate release composition and the second layer contains a sustained release composition.

In one embodiment, the active ingredient constitutes at least 20-30%, 30-60%, or 70% by weight of the sustained release composition, with the remainder of the composition being excipients, such as fillers, lubricants, polymers, etc. The polymer may be present in one embodiment in an amount of 5-20 wt.% based on the weight of the sustained release composition, and in one embodiment 7-10 wt.% based on the weight of the sustained release composition, and in one embodiment 10 -16.5 wt.% based on the weight of the sustained release composition. In one embodiment, the polymer is a cellulosic polymer, such as Methocel K4M, and is present at about 10 wt%. The sustained release composition can be prepared by direct compression or wet granulation.

The composition may be compressed into tablets or may be included directly in food. Such

- 38 045546 compositions must contain at least 0.1% of the active compound. The percentage in compositions and preparations may vary, for example, from about 2 to about 60 wt.% based on the weight of the composition or preparation.

Excipients include, but are not limited to, one or more pharmaceutically acceptable inert diluents; digestible edible carrier; disintegrant to facilitate disintegration, e.g. modified cellulose derivatives, modified starch derivatives, etc., it should be noted that those skilled in the art will appreciate that other ingredients, including binders and lubricants, can also affect the dissolution profile dosage form; gelatin capsule with hard or soft shell; dicalcium phosphate; a binder such as gum tragacanth, gum acacia, corn starch or gelatin; a leavening agent such as corn starch, potato starch, alginic acid, etc.; a lubricant such as magnesium stearate; a sweetener such as sucrose, lactose or saccharin; fragrance such as peppermint, oil of wintergreen, cherry fragrance; one or more surfactants such as ionic, non-ionic surfactants and/or bile salts, wherein anionic surfactants include sodium alkyl sulfate (sodium lauryl sulfate) and sulfosuccinate derivatives such as sodium docusate, non-ionic surfactants include complex polyoxyethylene sorbitan fatty acid esters (polysorbates) such as TWEEN® 20, TWEEN® 80, TWEEN® 40, SPAN® 20, polyethylene glycol fatty acid esters such as GELUCIRE® 44/14, GELUCIRE® 50/13, saturated polyglycolysed (including mono-, di- or tri-)glycerides, medium chain monoglycerides (6-10 carbons) such as glyceryl monocaprylate (IMWITOR® 308), glyceryl monocaproate (CAPMUL® MSM C-8), glyceryl caprylate/caprate (CAPMUL® MSM) , polyoxyethylene glyceryl caprylate and polyoxyethylene glyceryl caproate (LABRASOL®), medium chain fatty acid esters such as glyceryl tricaprate and glyceryl tricaprylate (MIGLYOL® 612), ethylene oxide and propylene oxide block polymers, polyoxyethylene-polyoxypropylene block copolymers such as Poloxamer 188 (PL URONIC® F-68), Poloxamer 237 (PLURONIC® F-87), Poloxamer 338 (PLURONIC® F-108), Poloxamer 407 (PLURONIC® F-127), Poloxamer 124 (PLURONIC® L-44), polyoxyl stearate-polyethoxylated (40) stearic acid (MYRJ ® 52), ethoxylated castor oil-polyethoxylated (60) hydrogenated castor oil (CREMOPHOR® EL), ethoxylated hydrostearic acid-polyethylene glycol 660 hydroxystearate (SOLUTOL® HS 15), polyoxyethylene alkyl ethers (12-18 carbons) such as polyoxyl 20 cetostearyl ether ( ATLAS® G-3713), polyoxyl 10 oleyl ether (BRIJ® 96, BRIJ® 97, Oleth 10), polyethylene glycol ether (TRITON™ X-100, TRITON™ X-114, TRITON™ X-405, TRITON™ N-101 ) and lecithins such as phospholipids (dimyristoyl DL-alpha-phosphatidylcholine), bile salt surfactants including deoxycholic acid, sodium deoxycholate, cholic acid, sodium taurocholate; etc. The capsule dosage form may also contain a liquid carrier. Other substances may be present to coat the dosage form or to otherwise modify its physical form, for example, tablets, pills or capsules may be coated with shellac and/or sugar. The syrup or elixir may contain the active substance, sucrose as a sweetener, methyl and propyl parabens as preservatives, coloring and flavoring.

In embodiments, other active agents may be included in the composition.

In one embodiment, the dosage forms are liquid-filled soft gel capsules containing excipients that contain lipids, surfactants and solvents. Capsules may contain immediate release, delayed release, extended release or controlled release compositions.

The composition may contain excipients such as one or more fatty acids. The method involves dissolving, melting or suspending a poorly water-soluble active substance in one or more fatty acids, conjugated fatty acids, (semi-)solid surfactants having a high HLB value, and/or hydrophilic polymers. Suitable fatty acids include C ₁₀ -C ₁₈ fatty acids, preferably C ₁₆ -C ₁₈ fatty acids. Suitable conjugated fatty acids include C ₁₀ -C ₁₈ fatty acids, preferably C ₁₆ -C ₁₈ fatty acids conjugated to glycerol (eg monoglycerides), monosaccharides and/or polyethylene glycol (PEG). Suitable hydrophilic polymers include poloxomers and poloxamines.

Suitable fatty acids include C ₁₀ -C ₁₈ fatty acids, more preferably C ₁₆ -C ₁₈ fatty acids. Examples of fatty acids include, but are not limited to, dodecanoic (lauric) acid, tetradecanoic (myristic) acid, hexadecanoic (palmitic) acid, heptadecanic (margaric) acid, octadecanoic (stearic) acid, eicosanoic (arachidic) acid, docosanoic (behenic) acid, tetracosanoic (lignoceric) acid, hexacosanoic (cerotinic) acid, heptacosanoic (carboceric) acid, octacosanoic (montanoic) acid, triacontanoic (melissic) acid, dotriacontanoic (laceric) acid, tritriacontanoic (ceromelissic) acid, tetratriacontane ( heddic) acid and pentatriacontanoic (ceroplastic) acid. The fatty acids may be saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, or combinations of the above.

Oils, for example vegetable oils such as soybean oil, can be used alone or in combination with the coating agents listed above. Soybean oil contains 14.4% saturated fatty acids, 23.3% monounsaturated fatty acids such as oleic acid, and 57.9% polyunsaturated fatty acids such as linoleic acid and alpha linoleic acid.

In one embodiment, the fatty acid is covalently linked to glycerol, a monosaccharide such as sorbitol or sorbitan, a polyalkylene oxide such as polyethylene glycol and polypropylene glycol, or combinations thereof. These substances are called conjugated fatty acids. Suitable conjugated fatty acids include, but are not limited to, polyethylene glycol fatty acid esters such as those commercially available under the trade name GELUCIRE®, sorbitan fatty acid esters such as sorbitan monostearate, glycerol fatty acid esters of those listed above fatty acids such as glycerol behenate and glyceryl monostearate, and combinations thereof.

The range of fatty acid concentrations is from about 1 to about 20% by weight of the composition, preferably from about 5 to about 15% by weight of the composition (microparticles and carrier).

The water-insoluble active agent may be coated with one or more surfactants, alone or in combination, and one or more fatty acids or conjugated fatty acids and/or one or more hydrophilic polymers. In one embodiment, the surfactant has an HLB value greater than about 10, greater than about 12, greater than about 14, or greater than about 16 (on a scale of 1-18). Surfactants having the desired HLB are known in the art. The surfactant may be anionic, cationic or nonionic. In one embodiment, the surfactant is a nonionic surfactant.

Examples of such surfactants include, but are not limited to, polysorbate 20, 40 and 80 (marketed as TWEEN®), polyoxyethylene monostearate, certain sugar esters such as sucrose monolaurate, ethoxylated nonylphenols, alpha olefin sulfonates, ethoxylated tallow amines , ethylene oxide/propylene oxide block copolymers, ethoxylated soy amines, fatty acids and alcohols, polyethoxylated castor oil, polysorbates, polyoxyethylene alkyl ethers and polyoxyethylene stearates.

In one embodiment, the surfactant is a high HLB surfactant containing a fatty acid chain. Suitable surfactants include, but are not limited to, polyethoxylated castor oil, polysorbates, polyoxyethylene alkyl ethers and polyoxyethylene stearates.

Derivatives of polyoxyethylene castor oil contain predominantly ricinoleylglycerol, ethoxylated with 30-50 molecules of ethylene oxide. Polysorbates or polyoxyethylene sorbitan fatty acid esters are a series of partial fatty acid esters of sorbitol and its anhydrides copolymerized with approximately 20, 5 or 4 moles of ethylene oxide for each mole of sorbitol and its anhydrides. The resulting product is a mixture of molecules having a wide range of molecular weights. Polyoxyethylene alkyl ethers are a series of polyoxyethylene glycol ethers of linear fatty alcohols (n-alcohols) such as lauryl, myristyl, cetyl and stearyl alcohols. Polyoxyethylene stearates are produced by polyethoxylation of stearic acid.

Without wishing to be bound by theory, it is believed that the hydrophilic portion of the surfactant enhances the compatibility of the active agent with the aqueous dissolution medium in vitro or in vivo and that the fatty acid side chain enhances absorption through fatty acid oxidation. During fatty acid oxidation, intracellular Ca ²⁺ is taken up, which causes the gap junctions of cells to widen, allowing the active substance to pass between cells. In addition, such coated particles may be more stable than the drug alone, for example by preventing oxidation of the active substance.

The surfactant concentration is from about 1 to about 50%, preferably from about 5 to about 15%, based on the weight of the composition (microparticles and carrier).

Suitable hydrophilic polymers include, but are not limited to, poloxamers, poloxamines, polyethylene glycols, polyvinyl alcohols, polyvinylpyrrolidone, poly(vinyl alcohol), cellulose derivatives such as hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, gelatin, carboxymethylcellulose, and polypeptides.

The concentration of hydrophilic polymer is from about 1 to about 50% by weight

- 40 045546 composition, more preferably from about 5 to about 15% based on the weight of the composition. If the hydrophilic polymer is polyethylene glycol, the concentration is from about 1 to about 80% by weight of the composition, from about 30 to about 60%, from about 35 to about 60%, or from about 40 to about 60% by weight of the composition (microparticles and carrier).

In one embodiment, microparticles are prepared by adding a mixture of drug and coating material(s) to a pharmaceutically acceptable carrier. In one embodiment, the carrier is a hydrophilic or lipophilic carrier. The resulting particles are suspended in a carrier. The carrier may be a single component or a mixture of components. The carrier may include solvents, surfactants or other excipients. Substances used as carriers can alter or modify the rate of drug release from the microparticles and/or the rate of drug dissolution. The compositions may exhibit a biphasic release profile due to the controlled release properties of the microparticles and the controlled release properties of the carrier. Changing the qualitative and quantitative composition of carrier substances may allow modulation of the release profile of the active substance. The carrier may contain one or more rate-controlling excipients that control the release of the active substance. Examples of rate-controlling excipients include, but are not limited to, glyceryl behenate, GELUCIRE®, CREMOPHOR®, hydrogenated vegetable oil, beeswax, cellulose polymers such as hypromellose, alginates, CARBOPOL®, and combinations thereof.

In one embodiment, the carrier is a hydrophilic carrier containing a surfactant having an HLB value greater than about 10, greater than about 12, greater than about 14, or greater than about 16, and/or is water soluble. Typical hydrophilic carriers include, but are not limited to, polyethylene glycols, polyoxyethylene-32 lauric acid glycerides (available from Abitech under the trade name ACCONON® M-44), polyoxyethylene-8 caprylic acid glycerides (available from Abitech under the trade name ACCONON® MC-8 ) and glycofurol. The hydrophilic carrier may also contain one or more miscible solvents such as glycerol, ethanol, glycofurol and caprylocaproyl macrogol-8 (available from Gattefosse S.A., Saint Priest, France under the trade name LABRASOL®).

In one embodiment, the hydrophilic carrier is water or alcohol. In another embodiment, the carrier is a mixture of hydrophilic carriers containing polyethylene glycol and, optionally, one or more surfactants and/or water. In a specific embodiment, the hydrophilic carrier is a mixture of PEG 400 (e.g., 57% by weight of the composition), water (e.g., 8% by weight of the composition), and TWEEN® 20 (e.g., 10% by weight of the composition) . The hydrophilic carrier may also contain CREMOPHOR® RH 40. The concentration of the hydrophilic carrier is typically from about 50 to about 85% by weight of the composition (microparticles and carrier), preferably from about 70 to about 80% by weight of the composition.

In another embodiment, the carrier is a lipophilic carrier. In a preferred embodiment, the lipophilic carrier has an HLB value of less than about 10 and/or is oil soluble. Typical lipophilic oil carriers include, but are not limited to, vegetable oils, medium chain mono-, di- and triglycerides, glyceryl stearates (available from Sasol under the trade name IMWITOR®), polyoxyethylated oleic glycerides (available from Gattefosse, SA., Saint Priest, France, under the name LABRAFIL®), mineral oil, mono- and diglyceride emulsifiers such as glyceryl monooleate, glyceryl monocaprate, glyceryl monocaprylate, propylene glycol monocaprylate and propylene glycol monolaurate (available from Abitec Corp., Columbus, Ohio, under the trade name CAPMUL®) and dimethylpolysiloxanes such as simethicone.

The concentration of lipophilic carrier is typically from about 10 to about 50% by weight of the composition (microparticles and carrier), preferably from about 5 to about 35% by weight of the composition.

The compositions described may contain one or more pharmaceutically acceptable excipients that are considered safe and effective and that can be administered to an individual without causing unwanted biological side effects or unwanted interactions. Typical additives include, but are not limited to, solvents, suspending agents, dispersants, buffers, pH modifying agents, isotonicity modifying agents, preservatives, antimicrobial agents, and combinations thereof.

Suitable additives for inclusion in the compositions described herein include, but are not limited to, antioxidants (eg, alpha-tocopherols such as vitamin E acetate, ascorbic acid, butylated hydroxyanisole, and butylated hydroxytoluene); polar solvents (eg water, propylene glycol and glycerin); hydrophobic solvents (e.g. corn oil, castor oil, soybean oil, olive oil, fish oil, peanut oil, peppermint oil, safflower oil, sesame oil, medium chain triglycerides, caprylic acid triglycerides, capric acid triglycerides, isolated from coconut oil or palm oil) and viscosity increasing agents (eg, gelatin, glycerin, carrageenan, colloidal silica, hydrogenated vegetable oil; povidone and propylene glycol alginate).

The microparticle compositions described herein are typically formulated for oral or parenteral administration. Suitable oral dosage forms include capsules such as hard or soft gelatin or non-gelatin capsules or oral suspensions or syrups (eg, FIG. 21). Suitable parenteral dosage forms include suspensions.

In one embodiment, the microparticle compositions (microparticles suspended in a hydrophilic or lipophilic carrier) are encapsulated in a capsule, such as a hard or soft capsule. Capsules can be prepared from natural and/or synthetic film-forming polymers. Suitable natural film-forming materials include, but are not limited to, gelatin. Non-gelatin capsules include, but are not limited to, capsules made from carrageenan, shellac, alginates, pectin and zeins. Suitable synthetic film-forming polymers include, but are not limited to, methylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, and acrylates such as poly(meth)acrylate.

The compositions may also be encapsulated in an enteric capsule, where the capsule is coated with an enteric coating, or the capsule shell contains an enteric polymer, as described in WO 2004/030658, Banner Pharmacaps, Inc.

Hard shell capsules are typically prepared by forming two capsule halves, filling one of the halves with a filling solution, and then sealing the capsule halves together to form the finished capsule. Soft gelatin capsules are usually produced by encapsulation using a rotary die. Such processes are known in the art.

The capsule shell may contain one or more additives. Suitable coating additives include plasticizers, opacifiers, colorants, humectants, preservatives, flavors and buffering salts and acids, and combinations of such substances.

Plasticizers are chemicals added to gelatin to make the material softer and more flexible. Suitable plasticizers include, but are not limited to, glycerin, sorbitol solutions, which are mixtures of sorbitol and sorbitan, and other polyols such as propylene glycol and maltitol, or combinations thereof.

Opacifiers are used to make the capsule shell opaque when the encapsulated actives are photosensitive. Suitable opacifiers include titanium dioxide, zinc oxide, calcium carbonate, and combinations thereof.

Dyes can be used for marketing purposes and product identification/differentiation. Suitable dyes include synthetic and natural dyes and combinations thereof.

Humectants can be used to suppress the water activity of the soft gel. Suitable humectants include glycerin and sorbitol, which are often components of the plasticizer composition. Due to the low water activity of dried, properly stored soft gelatin capsules, the greatest risk from microorganisms comes from mold and yeast. Therefore, preservatives may be included in the capsule shell. Suitable preservatives include alkyl esters of p-hydroxybenzoic acid such as methyl, ethyl, propyl, butyl and heptyl esters (collectively known as parabens) or combinations thereof.

Fragrances can be used to mask the unpleasant odors and tastes of fill compositions. Suitable fragrances include synthetic and natural fragrances. The use of fragrances can be problematic due to the presence of aldehydes, which can cross-link gelatin. Therefore, buffer salts and acids can be used in conjunction with fragrances that contain aldehydes to inhibit gelatin cross-linking.

Medium chain triglycerides can also be used. In the context of the present invention, the term medium chain triglycerides means C ₆ - ₁₂ ester chains formed by esterification of glycerol with three fatty acids. There are various sources of medium chain triglycerides such as coconut oil, palm oil, etc. Fractionated coconut oils are the most commonly used sources for medium chain triglycerides. Examples of commercially available medium chain triglycerides may include MIGLYOL® 810, 812 or 881, manufactured by Sasol Germany GMBH, CARTEX® 300, 355 or 810D, manufactured by Abitec Corporation, NEOBEE® M5, manufactured by Stepan Company, CRODAMOL® GTC/C, manufactured by Croda Inc, and LABRAFAC® Lipophile WL 1349, manufactured by Gattesfosse Group. In one illustrative embodiment, the medium chain triglyceride may include CARTEX® 355, which is a caprylic (C8)/capric (C10) acid triglyceride.

Various amounts of medium chain triglycerides may be included in the pharmaceutical composition. In one or more embodiments, the pharmaceutical composition may comprise from about 50 to about 95% by weight medium chain triglycerides or from about 85 to about 95% by weight medium chain triglycerides. Additionally, in illustrative embodiments, the pharmaceutical composition may include from about 100 to about 300 mg, or from about 200 to 300 mg of medium weight triglycerides, or from about 225 to 275 mg of medium weight triglycerides, or about 250 mg of medium chain triglycerides.

Like medium chain triglycerides, medium chain monoglycerides and medium chain diglycerides are C ₆ - ₁₂ ester chains formed by esterification of glycerol with one fatty acid or two fatty acids, respectively. Examples of commercially available medium chain mono/diglycerides may include CAPMUL® products manufactured by Abitec. The use of medium chain mono/diglyceride compounds, which also include medium chain triglycerides, such as the commercially available compositions IMWITOR®, manufactured by Sasol, is also contemplated.

In illustrative embodiments, the medium chain mono/diglycerides may include CAPMUL® MCM, which includes medium chain caprylic (C8)/capric (C10) acid mono/diglycerides. Although all grades of the CAPMUL® MCM product line are suitable for use in the present invention, such as National Formulary (NF) or CAPMUL® MCM EP, it may be desirable to use the EP grade since it includes 3% glycerol, whereas the NF grade includes 7%. glycerin.

In accordance with one or more embodiments, the pharmaceutical composition may include from about 5 to about 25 wt.% medium chain mono/diglycerides or from about 5 to about 15 wt.% medium chain mono/diglycerides. Additionally, in illustrative embodiments, the pharmaceutical composition may include from about 20 to about 50 mg by weight of medium chain mono/diglycerides, or from about 25 to about 30 mg by weight of medium chain mono/diglycerides, or about 25 mg by weight of medium chain mono/diglycerides .

Without being bound by any theory, the mixture of medium chain triglycerides and medium chain mono/diglycerides is essential for the bioavailability of the active ingredient in liquid-filled hard gel capsule formulations. While a soft gel capsule may contain only medium chain mono/diglycerides, a hard gelatin capsule with only medium chain mono/diglycerides may not provide the necessary physical stability of the finished dosage forms. However, a mixture of medium chain triglycerides and medium chain mono/diglycerides in a hard gelatin capsule can provide the required product stability, solubility and bioavailability of the active pharmaceutical ingredient. Therefore, in accordance with the present invention, the ratio by weight of medium chain triglycerides and medium chain mono/diglycerides promotes the solubility and stability of the active pharmaceutical ingredient (eg, dutasteride) in the non-emulsified mixture before and after adding the mixture to the capsule. Medium chain triglycerides and medium chain mono/diglycerides may be present in a weight ratio of from about 10:1 to about 5:1 or from about 10:1 to about 7:1.

In addition to the above components, other excipients known to those skilled in the art may be used, for example, excipients used in an oral composition may include diluents, binders, lubricants, disintegrating agents, flavoring agents, coloring agents, stabilizers, glidants, plasticizers, preservatives, and sweeteners. .

Diluents may include liquid diluents such as any long chain triglyceride (peanut oil, almond oil, ground nut oil, palm oil, palm kernel oil, blackcurrant seed oil, rice bran oil, soybean oil, canola oil, corn oil, coconut oil, Cottonseed oil, castor oil, olive oil, Linn oils (Neem), sesame oil, primrose oil, vegetable oil, Lipex 108 (Abitec), wheat germ oil, fish oil, canola oil, sunflower oil and Saffola oil.In alternative options other diluents are contemplated, for example diluents selected from calcium aluminum silicates (SIPERNAT® 106PQ), calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrate, dextrose, fructose , lactitol, anhydrous lactose, lactose monohydrate, lactose dihydrate, lactose trihydrate, mannitol, sorbitol, starch, pregelatinized starch, sucrose, talc, xylitol, maltose, maltodextrin, maltitol, silicon dioxide, HPMC and combinations thereof.

When formulating the compositions, the route of administration, type of drug, inactive ingredients, release of the active substance, stability, scale, new methods of obtaining the active substance, new methods of formulation are taken into account.

In vivo efficacy assessment includes pharmacokinetic data such as pK/pD, such as _Tmax , _Cmax , plasma concentration curve, efficacy, side effects, etc.

Other release profiles include, but are not limited to, controlled release, enteric release, sustained release, rapid release, multiphase release, etc.

Other known and to be determined uses of the disclosed compositions of domperidone and deuterated domperidone are covered by the present invention.

Each of the referenced documents cited above, as well as those listed below, is incorporated herein by reference in its entirety:

Chang and Robinson, chapter 4: Sustained Drag Release from Tablets and

Particles Through Coating, Pharmaceutical Dosage Forms: Tablets, vol. 3, Eds. Lieberman, Lachman, and Schwartz, Marcel Dekker, Inc., 1991.

Campbell and Sackett, Chapter 3: Film coating, Pharmaceutical Unit Operations:

Coating, edited by Avis, Shukla, and Chang, Interpharm Press, Inc, 1999.

Youssef et al., Identification of Domperidone Metabolites in Plasma and Urine of Gastroparesis Patients with LC-ESLMS/MS, Xenobiotica 43 (2013) 1073-1083.

Michaud et al., An Improved HPLC Assay with Fluorescence Detection for the

Determination of Domperidone and Three Major Metabolites for Application to in vitro Drag

Metabolism Studies, J. Chromatogr. B, 852 (2007) 611-616.

The disclosed compositions include a therapeutic amount of domperidone or deuterated domperidone or a pharmaceutically acceptable salt thereof and at least one excipient. The excipient may, for example, facilitate the delivery of the active substance. As disclosed above, other active agents may be included, such as analgesics, anesthetics, antioxidants, antimicrobials, antifungals, vitamins, etc.

One or more analgesics may be included in pharmaceutical compositions to provide relief from pain that may result from gastroparesis. Examples of analgesics include, but are not limited to, simple analgesics such as paracetamol or aspirin; non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, diclofenac sodium or naproxen sodium; and/or opioids such as codeine, dihydrocodeine, codeine phosphate, fentanyl, methadone, tramadol hydrochloride, dextropropoxyhydrchloride, morphine, oxycodone, buprenorphine or pethidine hydrochloride.

One or more anesthetics may be included in pharmaceutical compositions to induce temporary and reversible relief from pain caused by gastroparesis. Examples of anesthetics include, but are not limited to, one or more of lidocaine, benzocaine, bupivacaine, articaine, cocaine, etidocaine, flecamide, mepivacaine, pramoxine, prilocalne, procaine, chloroprocaine, hydroxyprocaine, proparacaine, ropivacaine, tetracaine, dyclonine, dibucaine, chloroxylenol , cinchocaine, dexivacaine, diamocaine, hexylcaine, levobupivacaine, propoxycaine, pyrrocaine, rhizocaine, rhodocaine and pharmaceutically acceptable derivatives thereof.

One or more antioxidants may be included in pharmaceutical compositions. Examples of antioxidants include, but are not limited to, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, diethylenetriaminepentaacetic acid (DTPA), edetates (EDTA), monothioglycerol, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA) , sodium bisulfite, triglycolamate, vitamin E or its derivative and propyl gallate.

In one embodiment, domperidone or deuterated domperidone and, optionally, any other agent are included in or applied to particles, including nanoparticles. Domperidone or deuterated domperidone particles may be suspended or dispersed in an aqueous medium. The particle size can thus vary from microparticles (µm) to nanoparticles (nm).

A human or other mammal suffering from gastroparesis or other gastrointestinal motility disorders can be treated by intermittent administration of the pharmaceutical compositions disclosed herein one or more times daily. Pharmaceutical agents, including domperidone or deuterated domperidone and any additional therapeutic agent, are present in the composition in an amount constituting a therapeutically effective dose. A therapeutically effective dose is an amount of a pharmaceutical agent that, when treated, results in some degree of symptomatic relief compared to the symptom status before administration of the agent.

The pharmaceutical compositions can be administered one to four times daily.

In one embodiment, domperidone or deuterated domperidone is administered in a range from about 0.1 to about 120 mg, or in a range from 0.01 to 12.0% w/w, or in a range from about 0.0014 to about 1 .71 mg/kg.

In other embodiments, domperidone or deuterated domperidone is administered in the range of about 0.5 to about 100 mg, or in the range of about 0.05 to about 10.0%, or in the range of about 0.007 to about 1.43 mg/kg . In one embodiment, domperidone or deuterated

- 44 045546 domperidone is administered in a range of from about 1 to about 60 mg, or from about 0.1 to about 6.0%, or from about 0.014 to about 0.86 mg/kg. In one embodiment, domperidone or deuterated domperidone is administered in a range of from about 2.0 to about 30 mg, or from about 0.2 to about 3.0%, or from about 0.028 to about 0.43 mg/kg. In one embodiment, domperidone or deuterated domperidone is administered in a range of from about 0.5 to about 120 mg, or from about 0.05 to about 12.0%, or from about 0.007 to about 1.71 mg/kg. In one embodiment, domperidone or deuterated domperidone is administered in a range of from about 2.0 to about 40 mg, or from about 0.2 to about 4.0%, or from about 0.028 to about 0.57 mg/kg. All % are given as w/w.

The compositions may also include excipients. Examples of excipients include, but are not limited to, binders, fillers, solvents, lubricants, antioxidants, buffering agents, salts, surfactants, vitamins, pigments, flavors, disintegrants and/or plasticizers.

Solid excipients can be added to the pharmaceutical composition and then crushed and formed into tablets. Typical solid excipients include, but are not limited to, sugars including lactose, sucrose, sucralose, mannitol or sorbitol; cellulose-based materials such as corn starch, wheat starch, rice starch, potato starch, gum tragacanth, gelatin, methylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose and/or sodium carboxymethylcellulose. Excipients known to disintegrate tablets after administration include, but are not limited to, agar, alginic acid and/or its salts, mannitol, microcrystalline cellulose, corn starch, citrus pulp, sodium lauryl sulfate, bentonite, sodium starch glycolate, calcium carboxymethylcellulose, clays, algins, gums, wood cellulose, powdered natural sponge and/or cation exchange resins.

The composition may include other excipients and additives to modify one or more characteristics of the composition, such as coverage, viscosity, palatability, etc. Palatability excipients may include, but are not limited to, sugars such as lactose, sucrose, sucralose, dextrose, mannitol or sorbitol; natural sweeteners such as honey; cellulose-based additives such as corn starch, wheat starch, rice starch; other sweeteners such as alitame, aspartame, cyclamic acid and their salts, dihydrochalcones, glycyrrhizinates, monellin, sodium saccharin, thaumatin or acesulfame potassium; and/or other sweeteners or flavorings.

Optional excipients, such as viscosity modifiers, can be added to the liquid composition to alter the flow characteristics of the composition. The flow characteristics can be modified to be incorporated into a specific application device or mechanism for applying the composition to the treatment site. Examples of viscosity modifiers include, but are not limited to, glycerin, carbomer homopolymer, carbomer copolymer, gum arabic, agar, magnesium aluminum silicate, sodium alginate, sodium stearate, kelp, bentonite, carbomer, carrageenan, locust bean gum, Irish moss, dextrose, furcellaran, gelatin, gatti gum, guar gum, sterculia gum, tragacanth gum, xanthan gum, hectorite, lactose, maltodextrin, mannitol, sucrose, sorbitol, honey, corn starch, wheat starch, rice starch, potato starch, polyethylene glycols, cellulose , ethylcellulose, ethylhydroxyethylcellulose, ethylmethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, poly(hydroxyethyl methacrylate), oxypolygelatin, pectin, polygelin, propylene carbonate, methyl vinyl ether/maleic anhydride copolymer (PVM/MA), poly(methoxyethyl methacrylate), poly(methoxyethoxy ethyl methacrylate), hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose (CMC) (including its salts), silicon dioxide, polyvinylpyrrolidone (PVP) and/or SPLENDA®.

Pharmaceutical compositions may also include one or more binders, fillers, solvents, lubricants, antioxidants, buffering agents, salts, surfactants, vitamins, pigments, flavors, disintegrants and/or plasticizers. Examples of binders include, but are not limited to, any of the previously disclosed starches such as corn starch, wheat starch, rice starch and/or potato starch, cellulose derivatives such as methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, etc., polyethylene oxide POLYOX™ polymers of any molecular weight or grade, irradiated or not, polyvinylpyrrolidone (PVP), AVICEL® microcrystalline cellulose powder, etc. Examples of fillers include, but are not limited to, any of the previously disclosed Sugars and starches, cellulose, calcium salts, diatomaceous earth and/or titanium dioxide. Examples of buffers include, but are not limited to, acetate buffers, citrate buffers and/or phosphate buffers.

The surfactants added to the pharmaceutical composition may be anionic, cationic, nonionic or zwitterionic. Examples of surfactants include, but are not limited to, sodium alkyl sulfates (for example, sodium dodecyl sulfate

- 45 045546 (SDS)), cationic surfactants, which are quaternary ammonium and pyridinium compounds, polysorbates, sorbitan esters, bile acids, bile salts, nonoxynol or polyoxytylene glycol fatty acid esters and/or poloxamers. Examples of lubricants include, but are not limited to, talc, hydrogenated fatty oils, magnesium stearate, calcium stearate and/or stearic acid. Fragrances may include natural or synthetic fragrances. Plasticizers include, but are not limited to, glycerin and sorbitol.

Pharmaceutical compositions for the treatment of gastroparesis and other gastrointestinal motility disorders with domperidone or deuterated domperidone can be formulated for topical oral administration to the mucosal surface. Mucoadhesive delivery technologies provide safe and effective delivery of domperidone or deuterated domperidone through the oral mucosa. These mucoadhesive delivery technologies include all methods of diffusion in the oral mucosa: (i) passive diffusion, including transcellular (through cells) and paracellular (where the substance passes through lipid-rich domains around cells), (ii) carrier-mediated transport, and (iii) endocytosis/exocytosis, when a substance is actively taken up and excreted by cells through the endocytic pathway. Bioadhesion, also known as mucoadhesion, defines the ability of a biological or synthetic substance to adhere or stick to the mucosa, resulting in the substance adhering to tissue for a long time. This ability provides drug delivery applications and increased drug bioavailability, which results from the increased time that the bioadhesive dosage form is in contact with absorbent tissues compared to the standard dosage form. For a material to be bioadhesive, it must interact with mucus. Mucus is a highly hydrated viscous anionic hydrogel layer that protects the mucous membrane. Mucin consists of flexible chains of glycoproteins.

In this embodiment, the pharmaceutical composition includes a therapeutic amount of domperidone or deuterated domperidone and any optional other active agent, if present, and at least one excipient, which may include a mucoadhesive or bioadhesive, to increase the duration of contact between the pharmaceutically active agent and the lining of the cavity mouth, as well as to increase mucosal absorption of the active substance. The absorbent surface is the tissue surface beneath the oral mucosa to which the pharmaceutically active agent is intended to be applied. The pharmaceutical compositions can be applied in the form of ointments, creams, lotions, gels, powders or pastes, and can be applied to the treated areas with or without the use of films or adhesive tapes or special adhesive dressings for pressure. The compositions may also include a carrier to facilitate administration of the composition to the oral mucosa.

Examples of mucoadhesive or bioadhesive excipients include, but are not limited to, polymers that are natural, synthetic or biological; lipids, phospholipids, etc. Examples of natural and/or synthetic polymers include cellulose derivatives such as methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxyethylmethyl microcrystalline cellulose, etc.; natural gums such as guar gum, xanthan gum, locust bean gum, karaya gum, wigum, etc.; polyacrylates such as CARBOPOL® polymers, polycarbophil, etc.; alginates, thiol-containing polymers, polyoxyethylenes, polyethylene glycols (PEGs) with a molecular weight preferably between 1000 and 40000 Da, linear or branched, dextrans with a molecular weight preferably between 1000 and 40000 Da from any source, block copolymers, for example combinations of lactic acid and glycolic acid, such as PLA, PGA, PLGA with different viscosity, molecular weight and ratios of lactic and glycolic acids; polyethylene glycol-polypropylene glycol block copolymers with any number and combination of repeating units, such as PLURONIC® block copolymers, TETRONIC® block copolymers or GENAPOL® block copolymers, a combination of the above copolymers linked either physically or chemically, for example, mixtures of PEG copolymers -PLA or PEG-PLGA. The bioadhesive may be selected from polyethylene glycols, polyoxyethylenes, polyacrylic acid polymers such as CARBOPOL® polymers (such as CARBOPOL® 71G, 934P, 971P 974P) and polycarbophils (such as NOVEON® AA-1, CA-1 and CA-2 polycarbophils ), cellulose and its derivatives, polyethylene glycol, CARBOPOL® polymers and/or cellulose derivative or combinations; soluble polyvinylpyrrolidone polymer (PVP), carbomer homopolymer, carbomer copolymer, one or more of maltodextrin, alginate, cross-linked alginate gel, water-swellable but water-insoluble fibrous cross-linked carboxy-functional polymer, hydrophilic polysaccharide resin, thiomers, e.g. thiolated chitosan , thiolated polycarbophil, thiolated alginate, thiolated cellulose derivatives, thiolated carboxymethylcellulose, thiolated polyacrylic acid or thiolated polyacrylates; lectin, hydroxypropyl methylcellulose (HPMC), cellulose derivatives, HPMA copolymers, water-dispersible

- 46 045546 licarboxylated vinyl polymer, cationic polymers, non-ionic polymers or anionic polymers. Cationic polymers include, but are not limited to, chitosan (Low Viscosity Wella), chitosan (High Viscosity Wella), chitosan (Dr. Knapczyk), daichitosan H, daichitosan VH, Sea Cure 240, Sea Cure 210+, chitosan (Sigma), a mixture of polycarbophil/diachitosan VH, DEAE-dextran and aminodextran. Nonionic polymers include, but are not limited to, Scleroglucan, He-starch and NPC. Anionic polymers include, but are not limited to, low, medium or high viscosity carboxymethylcellulose (CMC), pectin, xanthan gum and/or polycarbophil. In one embodiment, the mucoadhesive agent is a CARBOPOL® polymer and/or a cellulose derivative.

Chitosan, due to its mucoadhesive nature (Lehr et al. 1992) and favorable toxicological properties, is an absorption enhancer in the intestinal epithelium. Chitosan glutamate decreased transepithelial electrical resistance (TEER) of an in vitro cultured intestinal epithelial cell line (Caco-2) (Borchard et al., 1996) and increased the transport of hydrophilic molecules such as [ ¹⁴ C]mannitol, molecular weight (MW) 182. 2, and fluorescein-dextran (MW 4400) to a significant extent in Caco-2 cell monolayers (Artursson et al. 1994; Borchard et al., 1996; Schipper et al., 1996). Similarly, transport of the peptide drug 9-desglycinamide, 8-arginine vasopressin (DGAVP, MW 1412) was markedly increased after co-administration with chitosan glutamate in Caco-2 cell monolayers (Luessen et al. 1997). Chitosan salts such as chitosan glutamate and chitosan hydrochloride are used in vivo as absorption enhancers for peptide drugs. Nasal administration of insulin with chitosan glutamate significantly reduced blood glucose levels in rats and sheep (Illum et al. 1994), and intraduodenal application of buserelin (MW 1299.5) and chitosan hydrochloride in a gel formulation increased the absolute bioavailability of buserelin from 0.1 ± 0 .1 to 5.1±1.5% (Luessen et al. 1996a). These increases in absorption may be attributed to the effect of chitosan on the integrity of epithelial tight junctions. Tight cell junctions play an important role in maintaining the selective barrier function of cell membranes and in holding cells together to form a continuous cell layer through which even small molecules cannot penetrate. However, tight junctions are permeable to water, electrolytes, and other charged or uncharged molecules up to a certain size (Madara 1989; Wilson and Washington 1989). Tight junctions are known to respond to changes in calcium concentration, cyclic AMP (cAMP), osmolarity, pH, and cytoskeletal state (Cereijido et al., 1993).

Chitosan salts are proposed to open tight junctions in a concentration- and pH-dependent manner to allow paracellular transport of large hydrophilic compounds. The increase in transport of these compounds can be attributed to the interaction of the positively charged amino group at the C-2 position of chitosan with negatively charged sites on cell membranes and tight junctions of mucosal epithelial cells, allowing the opening of tight junctions. Chitosan glutamate is known to induce changes in F-actin distribution (Artursson et al. 1994). It is also known that pharmacological agents that interact with cytoskeletal F-actin simultaneously increase paracellular permeability (Meza et al. 1982). This is consistent with the hypothesis that F-actin is directly or indirectly associated with tight junction proteins such as ZO-1 (Madara, 1987). Schipper et al. (1997) showed that chitosan causes a redistribution of cytoskeletal F-actin and tight junction protein ZO-1. Confocal laser scanning microscopy has confirmed that chitosan is capable of opening tight junctions to allow paracellular transport of large hydrophilic compounds (Borchard et al. 1996; Schipper et al. 1997). Mucoadhesion may play an additional role in this process by increasing the residence time of drugs on cell surfaces.

In embodiments, the mucoadhesive/bioadhesive excipient is typically present in the range of about 1 to about 50% w/w, or in the range of about 1 to about 40% w/w, or in the range of about 2 to about 30% wt./wt. A single mucoadhesive or bioadhesive or combinations thereof may be used. Bioadhesion increases the residence time of the dosage form at the site of absorption and, therefore, can lead to increased bioavailability of the drug. The use of a mucoadhesive facilitates prolonged contact between the pharmaceutical composition and the oral mucosa. When the pharmaceutical composition comes into contact with the mucosa, moisture in the mucus plasticizes the mucoadhesive, which can then consolidate with the mucosa, forming weak bonds with glycoproteins in the mucus and/or mechanically adhering to glycoproteins and lipids in the mucus. The mucoadhesive can increase the contact time of the pharmaceutically active agent and the absorbent surface and can facilitate the absorption of the pharmaceutically active agents by the absorbent surface.

Aspects of.

Aspect 1. A dosage form of deuterated domperidone, including domperidoneD in an oral dosage form.

Aspect 2. Dosage form of Aspect 1, where a solution or suspension of deuterated domperidone is in a soft gelatin capsule, capsule or tablet providing a standard dose.

Aspect 3. A dosage form of deuterated domperidone comprising domperidone-b ₄ in a liquid-filled capsule containing excipients selected from the group consisting of lipids, fatty acids, surfactants, solvents and combinations thereof.

Aspect 4. A compound selected from the group consisting of formula 1, wherein at least one hydrogen atom is replaced by a deuterium atom, provided that six propyl hydrogen atoms are not replaced, compound 2, compound 3, compound 4, compound 5, and combinations thereof:

Aspect 5. A method for preparing the compound of Aspect 4, including the interaction of 1,2-diaminobenzene containing 0-4 deuterium atoms with a reactive carbonyl group to obtain a cyclic imide;

reacting the cyclic imide with a protecting group to obtain a monoprotected cyclic imide;

reacting a monoprotected cyclic imide with a 1,3-bifunctional propyl derivative containing 0-6 deuterium atoms to produce an intermediate;

reacting the intermediate with 5-chloro-1-(4-piperidinyl)-1,3-dihydro-2Hbenzimidazol-2-one and removing the protecting group either before or after reacting the intermediate with 5-chloro-1-(4-piperidinyl )-1,3-dihydro-2H-benzimidazol-2-one.

Aspect 6. A dosage form of domperidone comprising domperidone-b ₄ in a liquid-filled capsule containing excipients selected from the group consisting of lipids, fatty acids, surfactants, solvents and combinations thereof.

Aspect 7. Method for preparing compound 1 in accordance with Scheme 1:

comprising reacting 1,2-diaminobenzene containing 0-4 deuterium atoms with a reactive carbonyl group to produce a cyclic imide;

reacting the cyclic imide with a protecting group to obtain a monoprotected cyclic imide;

reacting a monoprotected cyclic imide with a 1,3-bifunctional propyl derivative containing 0-6 deuterium atoms to produce an intermediate;

reacting the intermediate with 5-chloro-1-(4-piperidinyl)-1,3-dihydro-2Hbenzimidazol-2-one and removing the protecting group either before or after reacting the intermediate with 5chloro-1-(4-piperidinyl)- 1,3-dihydro-2H-benzimidazol-2-one, wherein the 1,2-diaminobenzene contains at least one deuterium, or the 1,3-bifunctional propyl derivative contains at least one deuterium, or each of the 1,2-diaminobenzene and the 1,3-bifunctional propyl derivative contains at least one deuterium.

- 48 045546

Aspect 8. A method for preparing the deuterated domperidone compound of Aspect 4, comprising reacting 1,2-diaminobenzene containing 0-4 deuterium atoms with a reactive carbonyl group to produce a cyclic imide;

reacting the cyclic imide with a protecting group to obtain a monoprotected cyclic imide;

reacting a monoprotected cyclic imide with a 1,3-bifunctional propyl derivative containing 0-5 deuterium atoms to produce an intermediate;

reacting the intermediate with 5-chloro-1-(4-piperidyl)-1H-benzimidazol-2(3H)one and removing the protecting group either before or after reacting the intermediate with 5-chloro-1-(4-piperidyl)- 1H-benzimidazol-2(3H)-one, wherein 1,2-diaminobenzene contains at least one deuterium, or the 1,3-bifunctional propyl derivative contains at least one deuterium, or each of 1,2-diaminobenzene and 1, The 3-bifunctional propyl derivative contains at least one deuterium.

Aspect 9. Method for preparing deuterated domperidone, Compound 1, in accordance with Scheme 2:

comprising reacting 1,2-diaminobenzene containing 0-4 deuterium atoms with tetraethyl orthocarbonate to produce a protected cyclic imide;

reacting a protected cyclic imide with a 1,3-bifunctional propyl derivative containing 0-6 deuterium atoms to produce an intermediate and reacting the intermediate with 5-chloro-1-(4-piperidyl)-1H-benzimidazol-2(3H)one .

Aspect 10. Method for preparing deuterated domperidone, Compound 2, in accordance with Scheme 1:

comprising reacting 1,2-diaminobenzene containing 4 deuterium atoms with a reactive carbonyl group to produce a cyclic imide;

reacting the cyclic imide with a protecting group to obtain a monoprotected cyclic imide;

reacting a monoprotected cyclic imide with a 1,3-bifunctional propyl derivative to produce an intermediate;

reacting the intermediate with 5-chloro-1-(4-pineridyl)-1H-benzimidazol-2(3H)one and removing the protecting group either before or after reacting the intermediate with 5chloro-1-(4-piperidinyl)-1, 3-dihydro-2H-benzimidazol-2-one.

Aspect 11. Method for preparing deuterated domperidone, Compound 2, in accordance with Scheme 2:

comprising reacting 1,2-diaminobenzene containing 4 deuterium atoms with tetraethyl orthocarbonate to produce a protected cyclic imide;

reacting the protected cyclic imide with a 1,3-bifunctional propyl derivative to produce an intermediate; and reacting the intermediate with 5-chloro-1-(4-piperidyl)-1H-benzimidazol-2(3H)one.

- 49 045546

Aspect 12. 1-(3-chloropropyl)-4,5,6,7-tetradeutero-2-ethoxy-benzimidazole compound of formula 16, where R=H or D.

Aspect 13. 1-(3-chloropropyl)-4,5,6,7-tetradeutero-2-ethoxy-benzimidazole compound of formula 16, where R=D.

Aspect 14. Aspect 13 compound containing four deuterium atoms.

Aspect 15. A therapeutic method comprising administering to a patient in need thereof deuterated domperidone or a pharmaceutically acceptable salt thereof for the relief of a disorder selected from the group consisting of gastroparesis, nausea independent of gastroparesis, vomiting independent of gastroparesis, nausea associated with gastroparesis , vomiting associated with gastroparesis, gastroesophageal reflux disease, hypogalactia and combinations thereof, provided that deuterated domperidone is not Compound 6.

Aspect 16. The method of Aspect 15, wherein administration of d ₄ deuterated form of domperidone reduces the metabolism of domperidone to a greater extent than d ₆ deuterated form of domperidone.

Aspect 17. Method of Aspect 15, where the route of administration reduces the metabolism of domperidone.

Aspect 18. The method of Aspect 15, wherein the deuterated domperidone composition increases the bioavailability of domperidone.

Aspect 19. The method of Aspect 15, wherein the administered compounds are selected from the group consisting of compounds 2, compound 3, compound 4, compound 5 and combinations thereof.

Aspect 20. The method of Aspect 15, wherein deuterated domperidone is administered by a transdermal route.

Aspect 21. The method of Aspect 15, wherein the deuterated domperidone is administered by an administration route selected from the group consisting of oral administration, transdermal administration, parenteral administration, and combinations thereof.

Aspect 22. The method of Aspect 21, wherein the deuterated domperidone is administered orally in a dosage form selected from the group consisting of tablet, capsule, soft gelatin capsule, liquid, and combinations thereof.

Aspect 23. The method of Aspect 15, where deuterated domperidone is administered in the range of 0.5 to 120 mg.

Aspect 24. The method of Aspect 15, where deuterated domperidone is administered in the range of 0.05 to 12.0%.

Aspect 25. The method of Aspect 15, where deuterated domperidone is administered in the range of 0.07 to 1.71 mg/kg.

Aspect 26. The method of Aspect 15, where deuterated domperidone is administered in the range of 1 to 60 mg.

Aspect 27. The method of Aspect 15, where deuterated domperidone is administered in the range of 0.1 to 6.0%.

Aspect 28. The method of Aspect 15, where deuterated domperidone is administered in the range of 0.014 to 0.86 mg/kg.

Aspect 29. The method of Aspect 15, where deuterated domperidone is administered in the range of 2.0 to 40 mg.

Aspect 30. The method of Aspect 15, where deuterated domperidone is administered in the range of 0.2 to 4.0%.

Aspect 31. The method of Aspect 15, where deuterated domperidone is administered in the range of 0.028 to 0.57 mg/kg.

Aspect 32. The method of Aspect 15, where deuterated domperidone alleviates gastroparesis in the patient.

Aspect 33. The method of Aspect 15, wherein the deuterated domperidone alleviates at least one of nausea or vomiting as a separate disorder other than nausea or vomiting resulting from gastroparesis in the patient.

Aspect 34. The method of Aspect 15 wherein administration of domperidone is selected from the group consisting of an increased surface area form, a transdermal route, a lipid-based oral route, and combinations thereof.

Aspect 35. A method for facilitating the treatment of a disease in a patient, comprising administering to a patient in need thereof deuterated domperidone under conditions that increase the metabolism of domperidone relative to conditions resulting in normal metabolism of domperidone and/or increase the bioavailability of domperidone, provided that Deuterated domperidone is not compound 6.

Aspect 36. The method of Aspect 35, wherein administration of d4 deuterated domperidone reduces the metabolism of domperidone to a greater extent than _d6 deuterated domperidone.

Aspect 37. Method of Aspect 35, where the route of administration reduces the metabolism of domperidone.

Aspect 38. The method of Aspect 35, where the composition of deuterated domperidone increases the bioavailability of domperidone.

Aspect 39. The method of Aspect 35, wherein the administered compounds are selected from the group consisting of compounds 2, compound 3, compound 4, compound 5 and combinations thereof.

- 50 045546

Aspect 40. The method of Aspect 35, where deuterated domperidone is administered by transdermal route.

Aspect 41. The method of Aspect 35, wherein the deuterated domperidone is administered by an administration route selected from the group consisting of oral administration, transdermal administration, parenteral administration, and combinations thereof.

Aspect 42. The method of Aspect 39, wherein the deuterated domperidone is administered orally in a dosage form selected from the group consisting of tablet, capsule, soft gelatin capsule, liquid, and combinations thereof.

Aspect 43. The method of Aspect 35, wherein the increased surface area of the deuterated domperidone particulate composition increases the bioavailability of domperidone.

Aspect 44. The method of Aspect 35, where deuterated domperidone is administered in the range of 0.5 to 120 mg.

Aspect 45. The method of Aspect 35, where deuterated domperidone is administered in the range from 0.05 to 12.0%.

Aspect 46. The method of Aspect 35, where deuterated domperidone is administered in the range of 0.07 to 1.71 mg/kg.

Aspect 47. The method of Aspect 35, where deuterated domperidone is administered in the range of 1 to 60 mg.

Aspect 48. The method of Aspect 35, where deuterated domperidone is administered in the range of 0.1 to 6.0%.

Aspect 49. The method of Aspect 35, where deuterated domperidone is administered in the range of 0.014 to 0.86 mg/kg.

Aspect 50. Method of Aspect 35, where deuterated domperidone is administered in the range of 2.0 to 40 mg.

Aspect 51. The method of Aspect 35, where deuterated domperidone is administered in the range of 0.2 to 4.0%.

Aspect 52. The method of Aspect 35, where deuterated domperidone is administered in the range of 0.028 to 0.57 mg/kg.

Aspect 53. Method of Aspect 35, where domperidone alleviates gastroparesis in the patient.

Aspect 54. The method of Aspect 35, wherein domperidone alleviates at least one of nausea or vomiting as a separate disorder other than nausea or vomiting resulting from gastroparesis in the patient.

Aspect 55. The method of Aspect 35, wherein administration of domperidone is selected from the group consisting of an increased surface area form, a transdermal route, a lipid-based oral route, and combinations thereof.

The following examples are presented to illustrate some of the concepts described in this disclosure. Although each example is intended to represent particular specific embodiments of the composition, methods of preparation, and use, none of the examples should be construed as limiting the more general embodiments described herein.

In the following examples, care has been taken to ensure accuracy in terms of the numerical values used (eg quantities, temperature, etc.), but some experimental error and variation must be taken into account. Unless otherwise noted, temperatures are in degrees Celsius and pressures are at or near atmospheric pressure.

The following examples are not limiting. Examples 1-5 correspond to synthesis scheme 1. Examples 6-8 correspond to synthesis scheme 2.

From synthesis scheme 1.

Example 1. Preparation of 2,3-dihydro(4,5,6,7-O4)-1H-1,3-benzodiazol-2-one.

A 100 mL round bottom flask equipped with a magnetic stirrer and nitrogen inlet/outlet was charged with ₄ )benzene-1,2-diamine (1 eq., 2 g, 17.83 mmol) and 30 mL of anhydrous DMF, then stirred under a nitrogen atmosphere to dissolve before loading 1-(1H-imidazole-1-carbonyl)-1Himidazole (1 eq., 2.89 g, 17.83 mmol) and stirring at room temperature for 22 hours. The solvent was evaporated in vacuo with yielding a yellow thick oil, which was diluted in a minimal amount of dichloromethane (DCM) to crystallize. The desired solid was collected by suction filtration, washed with DCM and dried in vacuo to give 2.09 g (15.13 mmol, 85%) of the desired product.

Example 2. Preparation of tert-butyl 2-oxo-2,3-dihydro(4,5,6,7Iu ₄ )-III-1,3-benzodiazole-1carboxylate.

2,3-Dihydro(4,5,6,7-D4)-1H-1,3-benzodiazol-2-one (1 eq., 2.09 g, 15.13 mmol) and 40 ml of anhydrous DMF. To this stirred solution was added sodium hydride (1.1 eq., 197 mg, 8,200 mmol) portionwise and the reaction mixture was left under the same conditions for 1.5 hours. Di-tert-butyl dicarbonate (1 eq.) was then added dropwise. , 3.30 g, 15.13 mmol), dissolved in 8 ml of anhydrous DMF, and left to react for 3 hours. The reaction was completed and the mixture was treated with a saturated solution of NH ₄ Cl, followed by dilution with H ₂ O and extraction at

- 51 045546 aid 4x50 ml EtOAc. The organic fractions were combined, dried over Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo. The crude material thus obtained was purified by silica gel chromatography (Biotage ISOLERA™, KP-Sil 50g cartridge, eluting with a gradient of Cy:EtOAc from 90:10 pure AcOEt) to obtain 3.134 g (13.15 mmol, 87%) of the desired compound.

Example 3. Preparation of tert-butyl 3-(3-chloropropyl)-2-oxo-2,3-dihydro(D ₄ )-1H-1,3-benzodiazole-1carboxylate.

A three-neck round bottom flask was charged with tert-butyl 2-oxo-2,3-dihydro-1H-1,3-benzodiazole-1carboxylate (1 eq, 3.134 g, 13.15 mmol) in 60 mL anhydrous DMF and stirred at room temperature . Potassium carbonate (3 equiv., 5.452 g, 39.45 mmol) was added to this solution in portions and left under the same conditions for 30 minutes. Thereafter, 1-bromo-3-chloropropane (1 eq., 1.300 mL, 13.15 mmol) was added to this solution and stirred at room temperature overnight. The reaction was then quenched by dilution with ethyl acetate (EtOAc) and H2O. The layers were separated and the aqueous phase was extracted with 3x25 ml EtOAc, the organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated to dryness in vacuo. The crude material thus obtained was purified by silica gel chromatography (Biotage ISOLERA™, KP-Sil 50g cartridge, eluting with a gradient of 90:10 Cy:EtOAc to 1:1 Cy:EtOAc) to give the desired compound (3.929 g, 12.48 mmol, 95%).

Example 4. Preparation of 1-(3-iodopropyl)-2,3-dihydro(4,5,6,7-D ₄ )-1H-1,3-benzodiazol-2-one.

A 250 mL round bottom flask was charged with tert-butyl 3-(3-chloropropyl)-2-oxo-2,3-dihydro( _D4 )-1H1,3-benzodiazole-1-carboxylate (1 eq., 3.929 g, 12 .48 mmol) dissolved in 100 ml of acetonitrile and stirred at room temperature. Sodium iodide (4.5 eq., 8.417 g, 56.16 mmol) was added portionwise and the reaction mixture was refluxed overnight. After cooling to room temperature, the reaction mixture was filtered and the solvent was removed in vacuo. The crude material thus obtained was purified by silica gel chromatography (Biotage ISOLERA™, KP-Sil 100 g cartridge, eluting with a gradient from pure DCM to pure DCM:MeOH/1:1) to obtain the desired compound (3.631 g, 11.86 mmol, yield = 95%).

Example 5. Preparation of 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-D ₄ )-1H-1,3-benzodiazol-2-one (Compound 2).

A 500 mL round bottom flask was charged with 5-chloro-1-(4-piperidyl)-1H-benzimidazol-2(3H)-one (1.2 eq., 3.582 g, 14.23 mmol), then dissolved in 250 mL anhydrous THF and 25 ml anhydrous DMF. This solution was stirred under a nitrogen atmosphere at room temperature and a solution of 1-(3-iodopropyl)-2,3-dihydro(4,5,6,7-O ₄ )-1H-1,3-benzodiazol-2- she (1 eq., 3.631 g, 11.86 mmol) in 120 ml anhydrous THF for 10 min. The resulting yellow solution was stirred for 2 hours before adding potassium carbonate (1.5 eq., 2.458 g, 17.79 mmol) and stirring at room temperature for 48 hours until the yellow color disappeared. The reaction mixture was filtered, the solid was washed with EtOAc and the filtrate was concentrated to dryness in vacuo. The crude material thus obtained was purified by chromatography on silica gel (Biotage ISOLERA™, KP-Sil 340 g cartridge, eluting with a gradient of DCM:MeOH from 98:2 to DCM:MeOH/1:1). At the end of the purification process, 3.245 g (7.45 mmol, 64%) of the desired compound 2 was obtained as a white crystalline solid.

From synthesis scheme 2.

Example 6. Preparation of 4,5,6,7-tetradeutero-2-ethoxy-1H-benzimidazole (Compound 15).

A round-bottom flask equipped with a magnetic stirrer, thermocouple, refrigerator and nitrogen inlet/outlet was charged with 6.5 g (58 mmol, 1 eq.) of 2-amino-3,4,5,6-tetradeuteroaniline, which was suspended in 13 .3 ml (12.25 g, 63 mmol, 1.1 eq.) tetraethyl orthocarbonate and 0.3 ml (0.35 g, 5.8 mmol, 0.1 eq.) acetic acid. Absolute ethanol (19.5 ml) was added to the suspension and the resulting mixture was heated to reflux with stirring for 1 hour until HPLC analysis indicated that the reaction was complete. The orange solution was distilled to remove 20.5 ml of ethanol, then a solution of 13 ml of saturated sodium carbonate and 26 ml of water was added at a temperature slightly below boiling point to precipitate the product. After addition was complete, the suspension was cooled to room temperature and the solid was collected by vacuum filtration. The resulting wet cake was washed with water (26 ml), then dried in a vacuum oven overnight at 50°C to obtain 9.34 g (97.4%) of the desired product with a purity of >99.5% by HPLC.

Example 7 Preparation of 1-(3-chloropropyl)-4,5,6,7-tetradeutero-2-ethoxy-benzimidazole (Compound 16).

A round bottom flask equipped with a magnetic stirrer, a nitrogen inlet/outlet, and a condenser was charged with 9.2 g (55.3 mmol, 1.0 eq.) of Compound 15, potassium carbonate (15.3 g, 110.1 mmol, 2.0 equiv.), 1-bromo-3-chloropropane (8.21 ml, 83.1 mmol, 1.5 equiv.) and 55 ml methyl isobutyl ketone (MIBK). The resulting suspension was heated to reflux and stirred for 3 hours until HPLC analysis indicated that the reaction was complete. After cooling to room temperature, 36.8 ml of water was added and the mixture was stirred to dissolve the salt, then the phases were separated. The aqueous layer was extracted with MIBK (1x36.8 ml), the organic layers were combined

Claims (9)

taken, then concentrated to give an oil. MIBK (36.8 ml) was added to the oil and concentrated again. This procedure was repeated until ¹ H NMR analysis indicated that <1 mol% remained. 1-bromo-2-chloropropane. This oil was then used directly in the next step. Example 8. Preparation of 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-D ₄ )-1H-1,3-benzodiazol-2-one (Compound 2). 5-chloro-1-(4-piperidyl)-1H-benzimidazol-2(3H)-one (Compound 14, 13, 8 g, 54.9 mmol, 1.0 eq.), potassium iodide (9.1 g, 54.9 mmol, 1.0 eq.), potassium bicarbonate (5.5 g, 54.9 mmol, 1.0 eq.) and 60 ml of water. To this stirred suspension was added a solution of 13.33 g (54.9 mmol, 1.0 eq.) of compound 16 in 60 ml of isopropanol. After heating to reflux with a jacket temperature of 105°C, the reaction mixture was stirred at this temperature for 18 hours until HPLC analysis indicated that the reaction was complete. An additional 30 mL of water and 30 mL of isopropanol were added and reflux was continued for 20 min to dissolve the solids, then 36 mL of 4 M HCl (144 mmol, 2.6 eq.) was added to the refluxing mixture. Refluxing was continued for 2 hours until the deprotection reaction was completed. Still at reflux, the mixture was quenched to pH 11 with a solution of 12 M sodium hydroxide. Precipitation of the product was observed and the reaction was completed by cooling the mixture to 15°C and then the solid was collected by vacuum filtration. The wet cake was washed with water (3x51 ml) then dried in vacuo to obtain 20.37 g (86.3%) of the desired product with a purity of 94.5%. Purity can be increased to >97% by recrystallization from DMSO/water or trituration with IPA/water or MeOH/water. Example 9 Comparison of deuterated and non-deuterated domperidone. In this example, the activity of domperidone and b ₄ -domperidone was compared. Briefly, oral exposure to domperidone and deuterated domperidone ( _b4 -domperidone) was assessed in Beagle dogs following oral administration of suspension formulations containing domperidone or _b4 -domperidone and 0.5% methocel, 0.2% polysorbate 80 and 0. 72% lactic acid. Each compound was administered orally at a dose of 3 mg/kg, 10 mg/kg and 40 mg/kg. Blood samples were collected up to 24 hours after dosing and plasma domperidone concentrations were determined by LCMS/MS. Pharmacokinetic parameters were determined using Phoenix WinNonlin (v7.0). See fig. 22A and 22B. The embodiments shown and described in the specification are only specific embodiments carried out by the inventors, who are experts in the art, and are in no way limiting. Therefore, various changes, modifications or variations of these embodiments are possible without deviating from the spirit of the invention within the scope of the following claims. Each of the cited referenced documents is incorporated herein by reference in its entirety. CLAIM 1. A method of alleviating gastroesophageal reflux disease, functional dyspepsia, or nausea and vomiting associated with chemotherapy in a patient, comprising administering a therapeutically effective amount of a compound that is b ₄ -domperidone 2, or a pharmaceutically acceptable salt thereof, to the patient: (d ₄ -domperidone). 2. The method of claim 1, wherein the deuterated domperidone is administered orally, transdermally, parenterally, or using a combination of these routes of administration. 3. The method according to claim 2, wherein deuterated domperidone is administered orally. 4. The method according to any one of the preceding claims, wherein the therapeutically effective amount is in the range from 0.1 to 120 mg. 5. The method according to claim 4, wherein the therapeutically effective amount is in the range from 1 to 60 mg. 6. The method according to claim 5, wherein the therapeutically effective amount is in the range from 2.0 to 40 mg. 7. A method according to any of the preceding claims for alleviating gastroesophageal reflux disease. 8. Method according to any one of claims 1 to 6 for alleviating functional dyspepsia. 9. Method according to any one of claims 1 to 6 for alleviating nausea and vomiting associated with chemotherapy. -